This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, A. Articles by Papanikolaou, A. Search for Related Content PubMed PubMed Citation Articles by Arnold, A. Articles by Papanikolaou, A. Social Bookmarking                            What's this?

Cyclin D1 in Breast Cancer Pathogenesis

From the Center for Molecular Medicine, University of Connecticut School of Medicine, Farmington, CT

Address reprint requests to Andrew Arnold, MD, Center for Molecular Medicine, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06030-3101; e-mail: molecularmedicine{at}uchc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
Taking a perspective on available evidence that emphasizes relevance to human disease, cyclin D1 is solidly established as an oncogene with an important pathogenetic role in breast cancer and other human tumors. However, the precise cellular mechanisms through which aberrant cyclin D1 expression drives human neoplasia are less well established. Indeed, emerging evidence suggests that cyclin D1 might act, predominantly or at least in part, through pathways that do not involve its widely accepted function as a cell cycle regulator. Although therapeutic exploitation of the role of cyclin D1 as a molecular driver of breast cancer carries great promise, it is also suggested that direct targeting of the cyclin D1 gene or gene products may prove more successful than approaches that rely on arguably incomplete knowledge of the oncogenic mechanisms of cyclin D1.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
We have attempted to review the role of cyclin D1 in human neoplasia, with a specific focus on breast cancer pathogenesis, using a hierarchical approach that gives strongest weight to evidence derived from or validated in primary human tumors. This emphasis is intended to recognize appropriately the complexity of human cancer pathogenesis, and to highlight aspects that are, or are likely to become, clinically relevant. Our approach is not meant to deny the potential value of work in cultured cells, cell extracts, transfections with enforced gene overexpression, or genetically engineered mice; indeed, the latter in particular has much appeal as a mammalian whole-organism in vivo model. However, such systems bear the disadvantage of potentially obscuring the difference between "what can it do" versus "what does it do" in actual human tumorigenesis. Work in these in vitro or nonhuman in vivo systems is most valuable when explaining or supporting the pathogenetic significance of recurrent clonal lesions found in primary human tumors.

	CYCLIN D1 AS A HUMAN ONCOGENE

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
Recurrent clonal DNA alterations observed in primary human tumors are the end result of in vivo selection, and therefore constitute exceedingly powerful functional as well as structural evidence for a gene's importance in the development of neoplasia.^1-4 The cyclin D1 gene, located on human chromosome band 11q13, is an established oncogene for which genomic rearrangement or amplification leading to overexpression is commonly found as a clonal lesion in multiple types of human cancer. These tumor-specific alterations in the cyclin D1 gene reflect the critical selective advantage conferred by its overexpressed gene product and emphasize the importance of cyclin D1 as a driver of the neoplastic process. Indeed, the advantage of defining an oncogene as a gene in which specific DNA alterations (activating/gain of function) have been recurrently identified in human tumors is that any such gene is virtually certain to be pathogenetically important.^1-4 In contrast to the strong and convincing evidence that cyclin D1 is a human oncogene, there is considerable uncertainty about the precise downstream cellular mechanisms by which dysregulated cyclin D1 leads to neoplasia in vivo, its widely recognized role in cell cycle control notwithstanding (Fig 1).

View larger version (138K): [in this window] [in a new window]   Fig 1. Cyclin D1 gene amplification. cdk, cyclin-dependent kinase; pRB, retinoblastoma protein; E2F, E2 factor; ER, estrogen receptor; c/EBPß, CCAAT/enhancer binding protein.

The PRAD1 gene product was immediately recognized to have a domain of structural similarity to known eukaryotic cyclins,^5-7 was able to function like a cyclin (eg, by activating members of the cyclin-dependent kinase [cdk] family),⁹ and became more commonly known as cyclin D1. Indeed, although the recognized membership of the oncoprotein in the cyclin family was tremendously helpful in focusing experimental studies of its function into the cell cycle arena, this focus may have also delayed recognition of other functions of cyclin D1 that could be important in its ability to drive human neoplasia.^10,11

In another particularly direct demonstration of its primary role in human cancer, cyclin D1 has proven to be the BCL-1 oncogene, located at the breakpoint of the characteristic t(11;14)(q13;q32) clonal translocation in mantle-cell lymphomas^12-15 and in a subset of multiple myeloma.¹⁶ Importantly, breakpoints have been found within 1 to 2 kb of cyclin D1, and on both sides of the gene, essentially eliminating the alternative possibility that some nearby gene is the true BCL-1 oncogene. Thus, tumor-specific rearrangements of cyclin D1 clearly show that its activation confers a clinically significant selective advantage in human B-cell neoplasia and is important in tumor pathogenesis. It is, however, also worth noting that even in mantle-cell lymphoma (in which cyclin D1 rearrangement/activation is so prevalent as to suggest its near-necessity for yielding the mantle-cell phenotype),¹⁵ additional independent genetic lesions are also selected. This point emphasizes the general principle that development of a human malignancy requires multiple genetic hits, with no single lesion being both necessary and sufficient.

Cyclin D1 As a Breast Cancer Oncogene
Strong evidence implicates cyclin D1 amplification and overexpression as a driving force in human breast cancer. Approximately 13% to 20% of breast cancers possess three- to more than 10-fold amplification of DNA on 11q13.4 to 11q13.5.^17,18 Such amplification, or tandem extra copies, of a limited chromosomal region (the amplicon) initially occurs in one cell as an error in DNA replication (Fig 1). In the rare circumstances when a DNA amplification event confers a selective advantage on the cell and its progeny, the amplification will eventually emerge as an observable clonal alteration in the ensuing tumor's genome. A gene, the amplification of which contributes to the tumorigenic selective advantage, by definition, is an oncogene. However, amplicons are often large, containing many genes that are passively coamplified and provide no selective advantage; the difficulty of identifying the tumorigenically relevant driver oncogene(s) on a large amplicon is widely recognized. Indeed, for the gene-rich 11q13 region, evidence suggests that more than one distinct and independent amplicon, each with its own driver, may exist.^17-20 That said, cyclin D1 is the only gene on an 11q13 amplicon that has, to date, fulfilled all the criteria expected of such a pathogenetically key driver oncogene in breast cancer. First, across multiple tumors, cyclin D1 is consistently found within the borders of an amplicon (ie, it is a core gene).²¹ Second, with great regularity, cyclin D1 is strongly overexpressed when amplified.^21-26 Third, cyclin D1 overexpression causes mammary cancer in a physiologically relevant in vivo model, namely transgenic mice.²⁷ Notably, these mice required a long latency before developing mammary cancers, which some have interpreted to mean that cyclin D1 has less than robust strength as an oncogene.²⁸ To the contrary, however, the need for cooperativity with other oncogenic hits is entirely expected for an authentic human oncogene, is quite consistent with the role of cyclin D1 as a contributor in human cancer pathogenesis, and makes these mice an excellent model for key aspects of human breast cancer.

Furthermore, frequent and equally consistent involvement of cyclin D1 on an 11q13 amplicon in other cancers (eg, 30% to 35% of head and neck squamous cell and 35% of esophageal carcinomas),^24,29,30 plus its clear role as a clonally disturbed oncogene in other primary human tumors (eg, lymphoid and parathyroid), add support to its designation as a major driver oncogene in breast cancer. As discussed, other amplified genes on 11q13 may also contribute, but their ability to drive mammary cancer in a mammalian in vivo system remains to be demonstrated; some interesting candidates include EMS1 and EMSY.^18,19,31

If we take this human disease-oriented perspective, the interpretation of evidence from genetically engineered mice warrants elaboration. Such evidence can be tremendously valuable, and even crucial when distinguishing driver oncogenes from uninvolved passengers on tumor amplicons. However, because there are important differences between mice and humans, it must be re-emphasized that results from these models provide only secondary evidence that runs the risk of misinterpretation if not cross validated through analysis of human tissue and genetics. For example, the importance and significance of demonstrating that cyclin D1 can induce mammary cancer in transgenic mice depends strongly on the initial demonstration of the gene's central presence on clonal DNA amplicons in primary human breast cancers. In contrast, a number of overexpressed and/or mutant genes that can occasionally (eg, cyclin E)³² or even potently (eg, RAS)³³ cause mammary neoplasia in transgenic mice lack this validation in human tumors. To follow the given examples, the cyclin E gene is not amplified or rearranged,³⁴ nor are activating RAS mutations recurrently found in human breast cancers,³⁵ which suggests strongly that primary dysregulation of these genes does not provide a clinically important selective advantage in mammary tumorigenesis, the results from mouse modeling notwithstanding.

Cyclin D1 Overexpression Without Gene Amplification in Breast Cancer
Cyclin D1 protein overexpression is found in up to 50% of human breast cancers. In many of these tumors the overexpression cannot be explained by increased gene copy number, suggesting that pathogenic activation of cyclin D1 can occur via additional mechanisms, including transcriptional and post-transcriptional dysregulation.^{22,23,25,26,36-44}

The pattern of cyclin D1 overexpression in tissues along the spectrum from normal epithelium to invasive breast cancer^37,45-47 also suggests the involvement of cyclin D1 in the earliest stages of mammary carcinogenesis, and in both ductal and lobular subtypes.^37,38,45-47 One cannot be as certain that cyclin D1 is driving breast tumorigenesis in cancers with cyclin D1 protein overexpression but no gene amplification, compared with breast cancers in which cyclin D1 is overexpressed due to clonally selected gene amplification. On one hand, it is plausible that different, primary clonal lesions could secondarily lead to cyclin D1 activation and thus provide the cell with an alternate route toward achieving the same neoplastic common denominator. On the other hand, it is possible that such tumors, containing different primary oncogenic mutations, are not pathogenetically dependent on cyclin D1 despite its overexpression. The major significance of this unsettled issue, from a clinical perspective, relates to whether a future anti–cyclin D1 therapy will prove equally effective against overexpression-positive/amplification-negative tumors as it might against overexpression-positive/amplification-positive tumors.

	STRUCTURE AND EXPRESSION OF THE CYCLIN D1 GENE

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
Products of Alternative Splicing
The human PRAD1/CCND1 gene spans approximately 15 kb and includes five exons.⁴⁸ The gene encodes a 295-amino acid protein with molecular weight about 34 kd.⁵ Whereas most functional studies have been performed with this gene product, an alternatively spliced cyclin D1 transcript, termed transcript [b], has also been identified.^49-52 Unlike the originally reported gene product, now called transcript [a], transcript [b] results from failure of splicing at the exon 4-intron 4 junction. Therefore, the 3' end of the transcript [b] mRNA sequence continuing downstream into what would otherwise have been intron 4 while lacking exon 5.^49-52 Thus, the cyclin D1 isoform encoded by transcript [b], cyclin D1b, contains only 274 amino acids and has a different C-terminus from the transcript [a] -derived protein cyclin D1a (Fig 2).

View larger version (78K): [in this window] [in a new window]   Fig 2. Alternative splicing of cyclin D1.

For human breast cancer, transcript [b] is expressed in some primary tumors and breast cancer cell lines but at dramatically lower levels than transcript [a], and overexpression of cyclin D1 in breast cancer samples is primarily accounted for by transcript [a].⁵¹ Relative levels of cyclin D1a and D1b protein isoforms in primary breast cancers have not yet been reported, although cyclin D1b was not found in the ZR-75-1 breast cancer cell line known to bear cyclin D1 gene amplification and overexpression.⁵⁷ To date, only transcript [a] has been examined and found to drive mammary tumorigenesis in transgenic mice.²⁷ Still, cyclin D1b could also be making a significant contribution to breast oncogenesis,⁵² and its role deserves additional investigation in human tumors and in complex in vivo systems.

Exon 4 Polymorphism
A common polymorphism within cyclin D1, A/G at nucleotide 870 in exon 4, does not alter its encoded amino acid but has been reported to influence the ratio of alternatively spliced transcripts [a] and [b].⁵⁸ Results have been inconsistent, however, with the A allele favoring production of transcript [b] or transcript [a] in different studies and different tissues.⁵⁸ In addition, the A/A genotype has been associated with increased predisposition to a number of specific cancers, and/or to poor prognosis. However, the genotype at the 870A/G polymorphism does not appear to influence a woman's risk of breast cancer,^59,60 and it has not been determined whether the 870A/G genotype importantly alters the ratios of the cyclin D1 protein isoforms in breast cancer.

The Cyclin Box
Both isoforms of the cyclin D1 protein contain the so-called cyclin box sequence, a region of about 100 amino acids near the amino terminus. The sequence is fairly well conserved among all cyclins and is required for binding to their respective partner cdk. This sequence conservation does suggest that some aspect of cyclin D1 function relies on its ability to bind and activate a cdk. Whether such cdk dependence relates to the role of cyclin D1 in development, normal postnatal physiology, and/or tumorigenesis is still at issue.

	HOW DOES CYCLIN D1 ACTIVATION CAUSE BREAST CANCER?

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
Although the importance of cyclin D1 activation as a primary molecular cause of breast cancer is solidly established, the precise mechanisms through which cyclin D1 exerts its oncogenic action still require better definition. Resolving this issue carries important implications for devising new therapeutic strategies for breast cancer patients.

cdk-Mediated Effects on Cell Cycle Progression
Numerous studies, generally employing synchronized cultured cells and other in vitro systems, have led to the widely accepted view that the primary way in which cyclin D1 functions is by activation, as a regulatory subunit, of cdk4 and/or cdk6.⁹ Biochemically, cyclin D1–cdk complexes, followed in the cell cycle by analogous cyclin E-containing complexes, cause phosphorylation of retinoblastoma protein (pRB), the product of the retinoblastoma susceptibility gene, thereby inactivating the G₁-maintaining function of pRB. A noncatalytic function of cyclin D–cdk4/6 complexes in sequestering cdk inhibitor proteins p21 and p27 from the cyclin E–cdk2 complex has also been described.⁶¹ The ability of cyclin D1 to activate its cdk partner is antagonized by the p16^INK4a tumor suppressor. Although a huge body of evidence indicates that the main (and perhaps only) important role of cyclin D1 in the proliferation of cultured cells does indeed involve cdk activation and pRB inactivation, the same cannot be stated as definitively for the role of activated cyclin D1 in breast cancer or other primary human tumors.

The emphasis on cdk-dependent cell cycle actions as the major mechanism of cyclin D1 in human tumorigenesis has been argued on the basis that individual tumors tend to have a specific alteration of only one component of the cyclin D1/cdk/pRB/p16 pathway, suggesting a oncogenically relevant functional redundancy. On the other hand, there are many exceptions to this rule, and the functional equivalence of these lesions is further called into question by the major differences in their relative distributions across distinct types of primary tumors. It is also worth noting that cyclin D1 overexpression has not been associated with markers of tumor cell cycle activity in human breast cancers.³⁸ If we examine this problem more broadly, there are many genes that have been identified as key regulators of the cell cycle, but few have been established through recurrent clonal derangements to be human oncogenes or tumor suppressors. It is likely, therefore, that achieving a selective advantage requires something more than cell cycle misregulation. Thus the small subset designated cell cycle regulators with proven oncogenic significance contribute to tumorigenesis through special mechanisms in addition to (or possibly instead of) their recognized roles in the cell cycle. Beyond this theoretical argument, considerable evidence for specific non–cdk-dependent functions of cyclin D1 now exists.

Does Cyclin D1 Activation Contribute to Breast Cancer Through cdk-Independent Mechanisms?
As discussed, the recent accumulation of evidence that cyclin D1 may contribute to neoplasia through cdk (or cell cycle) -independent mechanisms is a departure from the widely accepted paradigm but in principle, is not surprising to those with a clinical perspective. A sampling of this intriguing evidence is described here (also see Coqueret⁴⁴), but it must also be emphasized that no definitive answers currently exist for the important questions about exactly how cyclin D1 exerts its oncogenicity in human neoplasia.

Evidence for cdk-independent mechanisms, in addition to the tissue type–specific skewing of distribution of mutations among cyclin D1, RB, and p16 genes in human tumors, includes in vitro observations of non–cell cycle effects of cyclin D1 on genomic instability,^62,63 an influence on DNA replication and repair in UV-treated fibroblasts,⁶⁴ a report of direct binding of cyclin D1 to proliferating cell nuclear antigen (PCNA),⁶⁵ and a link to the apoptotic pathway in neurons⁶⁶ and in cyclin D1–overexpressing MCF7 breast cancer cells.⁶⁷ Furthermore, in a series of breast cancer cell lines, overexpression of cyclin D1 was not related to cdk4 activity.⁶⁸ D-type cyclins bind to and repress the activity of a myb-like transcription factor, DMP1, by interacting with the DNA binding domain of DMP1, which in turn prevents its proper binding to target promoters.⁶⁹ A mutant cyclin D1 that is unable to activate cdk4 can still interact with DMP1 and inhibit its activity. Of great interest, DMP1 expression in transfected cells prevented S phase entry, and this DMP1-induced growth arrest could be overcome by the same mutant cyclin D1, indicating that the reversal of DMP1-induced growth arrest does not occur through its role as a cdk regulatory subunit.⁷⁰ Cyclin D1 strongly inhibits activity of the B-Myb transcription factor, not through cdk-dependent phosphorylation of B-Myb, but through formation of a specific complex between cyclin D1 and B-Myb.⁷¹ In addition, in cultured cells, the effect of cyclin D1 on transformation does not always rely on inactivation of pRB.^44,72,73 A variety of other transcriptional targets of cyclin D1 have been described, including the androgen receptor,⁷⁴ PPAR (peroxisome proliferator-activated receptor gamma),⁷⁵ and histone acetylases and deacetylases.⁴⁴

In breast cancer cell lines, overexpressed cyclin D1 has been shown to bind directly and activate the estrogen receptor alpha (ER) in a cdk- and pRB-independent fashion.^76,77 This fascinating finding, that overexpressed cyclin D1 can activate the ER in a hormonally independent fashion in vitro, and might thereby drive all of the key mitogenic effects of estrogen on breast epithelium, has the potential to add a crucial dimension to our understanding of mammary tumorigenesis. Although cyclin D1 overexpression is present across multiple histologic subtypes of breast cancer, a theme of commonality has been that the large majority of cyclin D1–overexpressing breast cancers are ER positive.^25,78,79 This strong association has been difficult to explain, given the prevalent concept that cyclin D1 expression is only a downstream consequence of estrogen-induced activation of the ER, a nuclear hormone receptor which functions as a transcription factor.^80-82 In that scenario, one might expect that tumors with more autonomous cyclin D1 expression due to gene amplification could bypass the need for functional ER, predicting an association between cyclin D1 overexpression and ER-negative breast cancer, which in fact is not observed. For example, almost all (94%) of the cyclin D1–positive breast cancers in one study were ER positive; in contrast, only 61% of cyclin D1–nonoverexpressing tumors were ER positive.²⁵ Such results raised doubt that the action of cyclin D1 as a downstream mediator of sex steroid mitogen-induced proliferation in cultured cell lines would fully explain its oncogenicity in breast cancer. The subsequent finding that cyclin D1 may act upstream or as a coregulator of ER activity,⁴⁴ as opposed to solely being a downstream target of ER-mediated activation, would provide an appealing explanation for the typical coexpression of ER in cyclin D1–positive breast cancers. In other words, cyclin D1 overexpression would bestow a selective advantage mainly in the presence of a serviceable ER.

Specifically, Zwijsen et al⁷⁶ and Neuman et al⁷⁷ tested the effect of cyclin D1 on ER transactivation by transfecting ER-positive breast cancer cells with a cyclin D1 expression vector, together with a reporter gene construct. Cyclin D1 directly interacted with liganded and unliganded ER to trigger binding of ER to an estrogen receptor response element and thereby increased reporter target gene transcription. Furthermore, the effect was not dependent on cyclin D1 interacting with cdk4 or pRB, given that it was reproduced with cyclin D1 mutants incapable of binding to cdk4 or pRb. Subsequent work showed that cyclin D1 not only interacted with the ER in cell lines but also with certain steroid receptor coactivators.^83,84 This raises the possibility that cyclin D1 may act as a bridge, recruiting essential coactivators to the ER even in the absence of estrogen. It has been suggested that cyclin D1 may exert its cdk-independent, transcriptional effects only when overexpressed, as in pathologic situations.¹⁰

A recent study has added considerable weight to the potential tumorigenic relevance of cdk-independent transcriptional functions of cyclin D1.¹¹ Lamb et al¹¹ determined the global patterns of gene expression in cultured breast cancer cells after enforced overexpression of either wild-type cyclin D1 or a mutant form unable to activate cdk4 (KE mutant). Strikingly, both wild-type and mutant cyclin D1 effected the same signature of major changes in downstream gene expression, suggesting that the observed effects of cyclin D1 overexpression were cdk4 independent. The expression of this set of cyclin D1 target genes was then examined across a large panel of primary human tumors, and a positive correlation with cyclin D1 expression was found. Thus, the expression signature demonstrated in vitro was cross validated in vivo, providing support for the presence of cdk-independent actions of cyclin D1 in human tumors. Furthermore, a focused look at whether expression of known E2F target genes (downstream in the cyclin D/p16/cdkpRBE2F pathway, driving the G₁ to S transition) would correlate with cyclin D1 expression in these human tumors proved negative, casting more doubt on the idea that cyclin D1 acts primarily as a cell cycle regulator in cancers. Interestingly, and in marked contrast, cyclin D3 expression correlated nicely with the E2F target genes, emphasizing the idea that cyclin D1 in vivo has unique functional attributes not shared by other cyclins, including other D-type cyclins. Indeed, analysis of these differences may uncover the key features that make cyclin D1, unlike other cyclins, a robust human oncoprotein. Finally, this study provided evidence that overexpression of the transcription factor C/EBPß is highly correlated with cyclin D1 expression in the same human cancer database, and that cyclin D1 acts on or with C/EBPß in regulating cyclin D1 target genes in vitro.¹¹

Clearly, the relevance of these alternative mechanisms of cyclin D1 action carry tremendous potential significance to human cancer, and the direct role of cdk-independent actions in tumorigenesis must be further examined in appropriately complex in vivo systems.

In Addition to Its Primary Role in Tumorigenesis, Does Cyclin D1 Mediate the Action of Other Oncogenes in Causing Breast Cancer?
Because cyclin D1 overexpression in breast cancers cannot always be attributed to clonally selected cyclin D1 DNA alterations such as gene amplification, it is conceivable that primary activation of other oncogenic/mitogenic pathways could provide an alternate route to tumorigenic cyclin D1 dysregulation. Consistent with this possibility, in vitro experiments have shown direct or indirect regulation of the cyclin D1 promoter, or of cyclin D1 expression, by ß-catenin, STAT5, STAT3, nuclear factor kappa B, ets-2, cyclic adenosine monophosphate–response element, tissue-coding factor/leukokinesis-enhancing factor, c-Jun, E2F-1, PPAR, calveolin-1, Ras signaling, and others.⁴⁴ It will be important to sort out the relevance of these cyclin D1 regulatory mechanisms to primary human neoplasia.

An interesting series of in vivo experiments have exploited genetically engineered cyclin D1–null mice. These animals exhibited normal development in most respects, a major exception being defective postnatal mammary development revealed by a lack of proliferation of alveolar epithelial cells in response to the sex steroid milieu of pregnancy.^85,86 Crossing of cyclin D1–null mice with transgenic mice that develop mammary cancer in response to oncogenes (Wnt1, v-Ha-ras, Neu/Erbb2, or Myc) overexpressed in mammary tissue showed that the cyclin D1–null background blocked mammary tumorigenesis driven by Ras or Neu, but not by Wnt1 or Myc.⁸⁷ These results have been widely interpreted to mean that mammary cancers driven by Neu or Ras pathway activation are dependent on cyclin D1 as an essential oncogenic intermediary in mice, and likely in humans. Similarly, it has been speculated that inhibitors of cyclin D1 could therefore effectively treat human breast cancers that overexpress NEU or RAS.

There are reasons, however, to view the common interpretation of these experiments with caution if not skepticism. First, cyclin D1 knockout mice are fundamentally experiments in development rather than tumorigenesis. Because these mice lack cyclin D1 throughout development, the specific mammary cell that is susceptible later in life to the action of a particular oncogene may not have developed or may be different from it would have been had development been normal. Second, even if Neu-driven mammary cancer could be shown to be crucially dependent on cyclin D1 in a background of normal development in mice, this may not be true in humans. Indeed, many or most NEU-activated human breast cancers are ER negative and would not be expected to overexpress cyclin D1, given that most cyclin D1–overexpressing breast cancers are ER positive; furthermore, Bieche et al²⁶ observed no link between cyclin D1 alterations and NEU overexpression in primary breast cancers.

Does Cyclin D1 Activation Cause Breast Cancer Solely by Leading to Increased Cyclin E Expression?
The action of cyclin D1 in fostering cell cycle progression has been viewed as preliminary to and necessary for the subsequent expression of cyclin E, but does cyclin D1 activation cause human breast cancer solely through a downstream activation of cyclin E expression? An affirmative answer to this question has been suggested by recent studies using genetically engineered mice. Cyclin E–encoding DNA under the control of the regulatory region of cyclin D1 was knocked in to cyclin D1–null mice, and the mammary developmental defect characteristic of cyclin D1–null mice was thereby abrogated.⁸⁸ This cyclin E knock-in also eliminated the resistance to Ras- or Neu-induced mammary cancer otherwise imparted by the cyclin D1–null background.⁸⁷ If ultimately shown to apply in human breast cancer, these results would suggest that the efficacy of an anticyclin D1 therapy might be enhanced by simultaneous targeting of cyclin E.

Again, however, there are strong reasons for caution before embracing these conclusions as relevant to human breast cancer. Although a compensatory upregulation of cyclin E was sometimes eventually able to overcome the blockade to an engineered mutant Neu-induced tumorigenesis imposed by the cyclin D1–null background in mice, this was not the case for the wild-type Neu sequence typically amplified in cancers.⁸⁹ Next, just as noted, these cyclin E knock-in experiments similarly fail to isolate the role of cyclin D1 in tumorigenesis from the effects of its loss during development. In addition, the ability of transgenically overexpressed cyclin E to drive mammary tumorigenesis in mice appears to be weaker than cyclin D1,²⁷ with a penetrance of only 10%.³²

Finally, and perhaps of most significance to the clinician, the roles of cyclin D1 and cyclin E in human breast cancer may well differ markedly from their roles in the mouse. The crucial point is that if cyclin E activation could drive human breast cancer as effectively as cyclin D1, or even at a less effective but still clinically relevant level, then robust evidence for cyclin E as a human breast oncogene should exist. To the contrary, however, such evidence is strikingly lacking in primary human breast cancers, nor has cyclin E core amplification, rearrangement, or other clonal activating mutation been recurrently identified in other human tumors. The strong implication is that cyclin E activation fails to confer a clinically important selective advantage on a mammary cell in the development of human breast cancer.

	PATHOGENESIS VERSUS PROGNOSIS

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
It is important to emphasize that the clear involvement of a gene in tumor pathogenesis is no guarantee of its utility as a prognostic marker, and vice versa. For example, involvement of a given gene may be so crucial to the development of a given type of tumor that interindividual differences in tumor behavior and prognosis will necessarily depend on other factors. For a given type of tumor, it can also be true that there are multiple alternative molecular means to the common end of tumor development. Perhaps for these reasons, cyclin D1 has both a clear, central role in breast cancer pathogenesis and an apparent but certainly less clear role as a clinically useful prognostic marker. Conversely, cyclin E (or E1) has been suggested to have major value as a prognostic marker,⁹⁰ although there is strikingly little evidence from primary human tumors that cyclin E is an oncogene.

The prognostic value of a marker depends on the available therapeutic armamentarium. For example, when some (but not all) studies defined cyclin D1 amplification or overexpression as marking a subset of ER-positive breast cancers as having a poorer prognosis than other ER-positive breast cancers,^91,92 a standard approach to treatment of the patients is assumed. However, molecular alteration in cyclin D1 could become an essential prognostic marker, if an effective therapy that specifically targeted cyclin D1 existed.

	CYCLIN D1 AS A THERAPEUTIC TARGET

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
The large number of breast (and other) cancers for which cyclin D1 activation is a pathogenetic cornerstone has appropriately attracted much attention in the search for improved therapeutics. Based in part on the widely accepted paradigm that the entire contribution of cyclin D1 to tumorigenesis is achieved through its activation of cdk4/6, much effort has been directed toward finding small molecule inhibitors of cdk, or activators of endogenous cdk inhibitors. For example, flavopiridol is a cdk-inhibitory agent in clinical trials.⁹³

However, if an important component of the oncogenic action of cyclin D1 is accomplished through cdk-independent mechanisms, therapeutic cdk inhibition might not be expected to be especially efficacious in cyclin D1–driven cancers. By the same reasoning, blocking cyclin D1 expression specifically and directly (by targeting the cyclin D1 gene, RNA, or protein) should increase the chances for therapeutic success in these tumors while advantageously avoiding the need for complete knowledge of the downstream effectors of cyclin D1 (Fig 1). Cell culture studies have raised the possibility that certain compounds might act in this way,^93-95 and approaches to blocking cyclin D1 expression using antisense, siRNA or related molecules also have conceptual appeal in specifically targeting the driving molecular lesion itself,^96-98 assuming in vivo use of these technologies becomes feasible.

Tumors bearing clonal genetic alterations in the cyclin D1 gene should be maximally susceptible to a highly specific anticyclin D1 therapy, akin to the efficacy of imatinib,⁹⁹ trastuzumab,¹⁰⁰ and gefitinib^101,102 against tumors with analogous clonal DNA lesions (BCR-ABL fusion,⁹⁹ HER2/neu amplification,¹⁰⁰ and EGFR mutation,^101,102 respectively) that speak to their central pathogenetic role in selection and, evidently, the ongoing viability of the tumor cell.¹⁰³ Earlier concern about potentially broad toxicity of a cell cycle agent has been diminished by the meager phenotype of cyclin D1–null animals and the new information on the cdk-independent actions of cyclin D1; nonetheless, achieving the ability to deliver an anti–cyclin D1 agent with high selectivity to tumor cells should certainly be advantageous. Finally, it might be expected that any successful anticyclin D1 therapy will find optimal use in a combination protocol, together with an agent that targets a different clonally selected cooperating gene (Fig 1) in the tumor, to eradicate the rare tumor cells that could escape a single agent through fortuitous mutation and subsequent selection.

In summary, because of its established role as a major human oncogene, the therapeutic exploitation of cyclin D1 holds tremendous promise and should be vigorously pursued. For many breast cancers, strong evidence of the role of cyclin D1 as a pathogenetic cornerstone suggests that appropriately selected tumors will be highly susceptible to future anti–cyclin D1 therapy.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by a grant CA55909 (to A.A.) from the National Institutes of Health and a postdoctoral fellowship from the Susan G. Komen Breast Cancer Foundation (to A.P).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION CYCLIN D1 AS A... STRUCTURE AND EXPRESSION OF... HOW DOES CYCLIN D1... PATHOGENESIS VERSUS PROGNOSIS CYCLIN D1 AS A... Authors' Disclosures of... REFERENCES

 
1. Tomlinson I, Bodmer W: Selection, the mutation rate and cancer: Ensuring that the tail does not wag the dog. Nat Med 5:11-12, 1999[CrossRef][Medline]

2. Devilee P, Cleton-Jansen AM, Cornelisse CJ: Ever since Knudson. Trends Genet 17:569-573, 2001[CrossRef][Medline]

3. Wang TL, Rago C, Silliman N, et al: Prevalence of somatic alterations in the colorectal cancer cell genome. Proc Natl Acad Sci U S A 99:3076-3080, 2002[Abstract/Free Full Text]

4. Haber D, Harlow E: Tumour-suppressor genes: Evolving definitions in the genomic age. Nat Genet 16:320-322, 1997[CrossRef][Medline]

5. Motokura T, Bloom T, Kim HG, et al: A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 350:512-515, 1991[CrossRef][Medline]

6. Xiong Y, Connolly T, Futcher B, et al: Human D-type cyclin. Cell 65:691-699, 1991[CrossRef][Medline]

7. Matsushime H, Roussel MF, Ashmun RA, et al: Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65:701-713, 1991[CrossRef][Medline]

8. Arnold A, Kim HG, Gaz RD, et al: Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 83:2034-2040, 1989

9. Sherr CJ: Cancer cell cycles. Science 274:1672-1677, 1996[Abstract/Free Full Text]

10. Bernards R: CDK-independent activities of D type cyclins. Biochim Biochim Biophys Acta 1424:M17-M22, 1999[Medline]

11. Lamb J, Ramaswamy S, Ford HL, et al: A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114:323-334, 2003[CrossRef][Medline]

12. Rosenberg CL, Wong E, Petty EM, et al: PRAD1, a candidate BCL1 oncogene: Mapping and expression in centrocytic lymphoma. Proc Natl Acad Sci U S A 88:9638-9642, 1991[Abstract/Free Full Text]

13. Williams ME, Swerdlow SH, Rosenberg CL, et al: Chromosome 11 translocation breakpoints at the PRAD1/cyclin D1 gene locus in centrocytic lymphoma. Leukemia 7:241-245, 1993[Medline]

14. Komatsu H, Iida S, Yamamoto K, et al: A variant chromosome translocation at 11q13 identifying PRAD1/cyclin D1 as the BCL-1 gene. Blood 84:1226-1231, 1994[Abstract/Free Full Text]

15. Swerdlow SH, Williams ME: From centrocytic to mantle cell lymphoma: A clinicopathologic and molecular review of 3 decades. Hum Pathol 33:7-20, 2002[CrossRef][Medline]

16. Bergsagel PL, Kuehl WM: Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma. Immunol Rev 194:96-104, 2003[CrossRef][Medline]

17. Courjal F, Cuny M, Simony-Lafontaine J, et al: Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: Definition of phenotypic groups. Cancer Res 57:4360-4367, 1997[Abstract/Free Full Text]

18. Schuuring E: The involvement of the chromosome 11q13 region in human malignancies: Cyclin D1 and EMS1 are two new candidate oncogenes—a review. Gene 159:83-96, 1995[CrossRef][Medline]

19. Hughes-Davies L, Huntsman D, Ruas M, et al: EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115:523-535, 2003[CrossRef][Medline]

20. Ormandy CJ, Musgrove EA, Hui R, et al: Cyclin D1, EMS1 and 11q13 amplification in breast cancer. Breast Cancer Res Treat 78:323-335, 2003[CrossRef][Medline]

21. Lammie GA, Fantl V, Smith R, et al: D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene 6:439-444, 1991[Medline]

22. Gillett C, Fantl V, Smith R, et al: Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54:1812-1817, 1994[Abstract/Free Full Text]

23. Bartkova J, Lukas J, Muller H, et al: Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57:353-361, 1994[Medline]

24. Jiang W, Zhang YJ, Kahn SM, et al: Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci U S A 90:9026-9030, 1993[Abstract/Free Full Text]

25. Zukerberg LR, Yang WI, Gadd M, et al: Cyclin D1 (PRAD1) protein expression in breast cancer: Approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol 8:560-567, 1995[Medline]

26. Bieche I, Olivi M, Nogues C, et al: Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays. Br J Cancer 86:580-586, 2002[CrossRef][Medline]

27. Wang TC, Cardiff RD, Zukerberg L, et al: Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669-671, 1994[CrossRef][Medline]

28. Barnes DM, Gillett CE: Cyclin D1 in breast cancer. Breast Cancer Res Treat 52:1-15, 1998[CrossRef][Medline]

29. Gaffey MJ, Iezzoni JC, Meredith SD, et al: Cyclin D1 (PRAD1, CCND1) and glutathione-S-transferase pi gene expression in head and neck squamous cell carcinoma. Hum Pathol 26:1221-1226, 1995[CrossRef][Medline]

30. Callender T, el-Naggar AK, Lee MS, et al: PRAD-1 (CCND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma. Cancer 74:152-158, 1994[CrossRef][Medline]

31. Arnold A: The cyclin D1/PRAD1 oncogene in human neoplasia. J Investig Med 43:543-549, 1995[Medline]

32. Bortner DM, Rosenberg MP: Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol Cell Biol 17:453-459, 1997[Abstract]

33. Sinn E, Muller W, Pattengale P, et al: Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo. Cell 49:465-475, 1987[CrossRef][Medline]

34. Courjal F, Louason G, Speiser P, et al: Cyclin gene amplification and overexpression in breast and ovarian cancers: Evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. Int J Cancer 69:247-253, 1996[CrossRef][Medline]

35. Miyakis S, Sourvinos G, Spandidos DA: Differential expression and mutation of the ras family genes in human breast cancer. Biochem Biophys Res Commun 251:609-612, 1998[CrossRef][Medline]

36. Hosokawa Y, Arnold A: Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells: Analysis of allele-specific expression. Genes Chromosomes Cancer 22:66-71, 1998[CrossRef][Medline]

37. Steeg PS, Zhou Q: Cyclins and breast cancer. Breast Cancer Res Treat 52:17-28, 1998[CrossRef][Medline]

38. Oyama T, Kashiwabara K, Yoshimoto K, et al: Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast. Cancer Res 58:2876-2880, 1998[Abstract/Free Full Text]

39. Lebwohl DE, Muise-Helmericks R, Sepp-Lorenzino L, et al: A truncated cyclin D1 gene encodes a stable mRNA in a human breast cancer cell line. Oncogene 9:1925-1929, 1994[Medline]

40. Albanese C, Johnson J, Watanabe G, et al: Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270:23589-23597, 1995[Abstract/Free Full Text]

41. Albanese C, D'Amico M, Reutens AT, et al: Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. J Biol Chem 274:34186-34195, 1999[Abstract/Free Full Text]

42. Albanese C, Wu K, D'Amico M, et al: IKKalpha regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf. Mol Biol Cell 14:585-599, 2003[Abstract/Free Full Text]

43. Mulloy R, Salinas S, Philips A, et al: Activation of cyclin D1 expression by the ERK5 cascade. Oncogene 22:5387-5398, 2003[CrossRef][Medline]

44. Coqueret O: Linking cyclins to transcriptional control. Gene 299:35-55, 2002[CrossRef][Medline]

45. Weinstat-Saslow D, Merino MJ, Manrow RE, et al: Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions. Nat Med 1:1257-1260, 1995[CrossRef][Medline]

46. Alle KM, Henshall SM, Field AS, et al: Cyclin D1 protein is overexpressed in hyperplasia and intraductal carcinoma of the breast. Clin Cancer Res 4:847-854, 1998[Abstract]

47. Rennstam K, Baldetorp B, Kytola S, et al: Chromosomal rearrangements and oncogene amplification precede aneuploidization in the genetic evolution of breast cancer. Cancer Res 61:1214-1219, 2001[Abstract/Free Full Text]

48. Motokura T, Arnold A: PRAD1/cyclin D1 proto-oncogene: Genomic organization, 5' DNA sequence, and sequence of a tumor-specific rearrangement breakpoint. Genes Chromosomes Cancer 7:89-95, 1993[Medline]

49. Betticher DC, Thatcher N, Altermatt HJ, et al: Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11:1005-1011, 1995[Medline]

50. Hosokawa Y, Tu T, Tahara H, et al: Absence of cyclin D1/PRAD1 point mutations in human breast cancers and parathyroid adenomas and identification of a new cyclin D1 gene polymorphism. Cancer Lett 93:165-170, 1995[CrossRef][Medline]

51. Hosokawa Y, Gadd M, Smith AP, et al: Cyclin D1 (PRAD1) alternative transcript b: Full-length cDNA cloning and expression in breast cancers. Cancer Lett 113:123-130, 1997[CrossRef][Medline]

52. Solomon DA, Wang Y, Fox SR, et al: Cyclin D1 splice variants: Differential effects on localization, RB phosphorylation, and cellular transformation. J Biol Chem 278:30339-30347, 2003[Abstract/Free Full Text]

53. Diehl JA, Sherr CJ: A dominant-negative cyclin D1 mutant prevents nuclear import of cyclin-dependent kinase 4 (CDK4) and its phosphorylation by CDK-activating kinase. Mol Cell Biol 17:7362-7374, 1997[Abstract]

54. Alt JR, Cleveland JL, Hannink M, et al: Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 14:3102-3114, 2000[Abstract/Free Full Text]

55. Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, et al: Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 22:6115-6118, 2003[CrossRef][Medline]

56. Lu F, Gladden AB, Diehl JA: An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 63:7056-7061, 2003[Abstract/Free Full Text]

57. Hosokawa Y, Joh T, Maeda Y, et al: Cyclin D1/PRAD1/BCL-1 alternative transcript [B] protein product in B-lymphoid malignancies with t(11;14)(q13;q32) translocation. Int J Cancer 81:616-619, 1999[CrossRef][Medline]

58. Howe D, Lynas C: The cyclin D1 alternative transcripts [a] and [b] are expressed in normal and malignant lymphocytes and their relative levels are influenced by the polymorphism at codon 241. Haematologica 86:563-569, 2001[Abstract/Free Full Text]

59. Krippl P, Langsenlehner U, Renner W, et al: The 870G>A polymorphism of the cyclin D1 gene is not associated with breast cancer. Breast Cancer Res Treat 82:165-168, 2003[CrossRef][Medline]

60. Grieu F, Malaney S, Ward R, et al: Lack of association between CCND1 G870A polymorphism and the risk of breast and colorectal cancers. Anticancer Res 23:4257-4259, 2003[Medline]

61. Sherr CJ, Roberts JM: CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev 13:1501-1512, 1999[Free Full Text]

62. Zhou P, Jiang W, Weghorst CM, et al: Overexpression of cyclin D1 enhances gene amplification. Cancer Res 56:36-39, 1996[Abstract/Free Full Text]

63. Lung JC, Chu JS, Yu JC, et al: Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability. Genes Chromosomes Cancer 34:276-284, 2002[CrossRef][Medline]

64. Pagano M, Theodoras AM, Tam SW, et al: Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev 8:1627-1639, 1994[Abstract/Free Full Text]

65. Xiong Y, Zhang H, Beach D: D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71:505-514, 1992[CrossRef][Medline]

66. Kranenburg O, van der Eb AJ, Zantema A: Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Embo J 15:46-54, 1996[Medline]

67. Coco Martin JM, Balkenende A, Verschoor T, et al: Cyclin D1 overexpression enhances radiation-induced apoptosis and radiosensitivity in a breast tumor cell line. Cancer Res 59:1134-1140, 1999[Abstract/Free Full Text]

68. Sweeney KJ, Swarbrick A, Sutherland RL, et al: Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells. Oncogene 16:2865-2878, 1998[CrossRef][Medline]

69. Hirai H, Sherr CJ: Interaction of D-type cyclins with a novel myb-like transcription factor, DMP1. Mol Cell Biol 16:6457-6467, 1996[Abstract]

70. Inoue K, Sherr CJ: Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism. Mol Cell Biol 18:1590-1600, 1998[Abstract/Free Full Text]

71. Horstmann S, Ferrari S, Klempnauer KH: Regulation of B-Myb activity by cyclin D1. Oncogene 19:298-306, 2000[CrossRef][Medline]

72. Hinds PW, Dowdy SF, Eaton EN, et al: Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci U S A 91:709-713, 1994[Abstract/Free Full Text]

73. Zwicker J, Brusselbach S, Jooss KU, et al: Functional domains in cyclin D1: pRb-kinase activity is not essential for transformation. Oncogene 18:19-25, 1999[CrossRef][Medline]

74. Petre CE, Wetherill YB, Danielsen M, et al: Cyclin D1: Mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem 277:2207-2215, 2002[Abstract/Free Full Text]

75. Wang C, Pattabiraman N, Zhou JN, et al: Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation. Mol Cell Biol 23:6159-6173, 2003[Abstract/Free Full Text]

76. Zwijsen RM, Wientjens E, Klompmaker R, et al: CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405-415, 1997[CrossRef][Medline]

77. Neuman E, Ladha MH, Lin N, et al: Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338-5347, 1997[Abstract]

78. Buckley MF, Sweeney KJ, Hamilton JA, et al: Expression and amplification of cyclin genes in human breast cancer. Oncogene 8:2127-2133, 1993[Medline]

79. Gillett CE, Lee AH, Millis RR, et al: Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. J Pathol 184:396-400, 1998[CrossRef][Medline]

80. Musgrove EA, Hamilton JA, Lee CS, et al: Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol 13:3577-3587, 1993[Abstract/Free Full Text]

81. Planas-Silva MD, Weinberg RA: Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol 17:4059-4069, 1997[Abstract]

82. Altucci L, Addeo R, Cicatiello L, et al: 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene 12:2315-2324, 1996[Medline]

83. Zwijsen RM, Buckle RS, Hijmans EM, et al: Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev 12:3488-3498, 1998[Abstract/Free Full Text]

84. McMahon C, Suthiphongchai T, DiRenzo J, et al: P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor. Proc Natl Acad Sci U S A 96:5382-5387, 1999[Abstract/Free Full Text]

85. Sicinski P, Donaher JL, Parker SB, et al: Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630, 1995[CrossRef][Medline]

86. Fantl V, Stamp G, Andrews A, et al: Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 9:2364-2372, 1995[Abstract/Free Full Text]

87. Yu Q, Geng Y, Sicinski P: Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017-1021, 2001[CrossRef][Medline]

88. Geng Y, Whoriskey W, Park MY, et al: Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:767-777, 1999[CrossRef][Medline]

89. Bowe DB, Kenney NJ, Adereth Y, et al: Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E. Oncogene 21:291-298, 2002[CrossRef][Medline]

90. Keyomarsi K, Tucker SL, Buchholz TA, et al: Cyclin E and survival in patients with breast cancer. N Engl J Med 347:1566-1575, 2002[Abstract/Free Full Text]

91. Borg A, Sigurdsson H, Clark GM, et al: Association of INT2/HST1 coamplification in primary breast cancer with hormone-dependent phenotype and poor prognosis. Br J Cancer 63:136-142, 1991[Medline]

92. Esteva FJ, Hortobagyi GN: Prognostic molecular markers in early breast cancer. Breast Cancer Res 6:109-118, 2004[CrossRef][Medline]

93. Senderowicz AM: Small molecule modulators of cyclin-dependent kinases for cancer therapy. Oncogene 19:6600-6606, 2000[CrossRef][Medline]

94. Hsiang CH, Straus DS: Cyclopentenone causes cell cycle arrest and represses cyclin D1 promoter activity in MCF-7 breast cancer cells. Oncogene 21:2212-2226, 2002[CrossRef][Medline]

95. Sawatsri S, Samid D, Malkapuram S, et al: Inhibition of estrogen-dependent breast cell responses with phenylacetate. Int J Cancer 93:687-692, 2001[CrossRef][Medline]

96. Sauter ER, Nesbit M, Litwin S, et al: Antisense cyclin D1 induces apoptosis and tumor shrinkage in human squamous carcinomas. Cancer Res 59:4876-4881, 1999[Abstract/Free Full Text]

97. Arber N, Doki Y, Han EK, et al: Antisense to cyclin D1 inhibits the growth and tumorigenicity of human colon cancer cells. Cancer Res 57:1569-1574, 1997[Abstract/Free Full Text]

98. Kornmann M, Arber N, Korc M: Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum. J Clin Invest 101:344-352, 1998[Medline]

99. Borthakur G, Cortes JE: Imatinib mesylate in the treatment of chronic myelogenous leukemia. Int J Hematol 79:411-419, 2004[Medline]

100. Nahta R, Esteva FJ: HER-2-targeted therapy: Lessons learned and future directions. Clin Cancer Res 9:5078-5084, 2003[Abstract/Free Full Text]

101. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004[Abstract/Free Full Text]

102. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004[Abstract/Free Full Text]

103. Weinstein IB: Cancer. Addiction to oncogenes: The Achilles heal of cancer. Science 297:63-64, 2002[Free Full Text]

Submitted May 11, 2004; accepted January 21, 2005.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				C. P. Masamha and D. M. Benbrook Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells Cancer Res., August 15, 2009; 69(16): 6565 - 6572. [Abstract] [Full Text] [PDF]

				I. Quiles, L. Millan-Arino, A. Subtil-Rodriguez, B. Minana, N. Spinedi, C. Ballare, M. Beato, and A. Jordan Mutational Analysis of Progesterone Receptor Functional Domains in Stable Cell Lines Delineates Sets of Genes Regulated by Different Mechanisms Mol. Endocrinol., June 1, 2009; 23(6): 809 - 826. [Abstract] [Full Text] [PDF]

				V. B. Wali, S. V. Bachawal, and P. W. Sylvester Combined Treatment of {gamma}-Tocotrienol with Statins Induce Mammary Tumor Cell Cycle Arrest in G1 Experimental Biology and Medicine, June 1, 2009; 234(6): 639 - 650. [Abstract] [Full Text] [PDF]

				S. Tejada, M. V. T. Lobo, M. Garcia-Villanueva, S. Sacristan, M. I. Perez-Morgado, M. Salinas, and M. E. Martin Eukaryotic Initiation Factors (eIF) 2{alpha} and 4E Expression, Localization, and Phosphorylation in Brain Tumors J. Histochem. Cytochem., May 1, 2009; 57(5): 503 - 512. [Abstract] [Full Text] [PDF]

				P. J. Day, A. Cleasby, I. J. Tickle, M. O'Reilly, J. E. Coyle, F. P. Holding, R. L. McMenamin, J. Yon, R. Chopra, C. Lengauer, et al. Crystal structure of human CDK4 in complex with a D-type cyclin PNAS, March 17, 2009; 106(11): 4166 - 4170. [Abstract] [Full Text] [PDF]

				R. Saab, C. Rodriguez-Galindo, K. Matmati, J. E. Rehg, S. H. Baumer, J. D. Khoury, C. Billups, G. Neale, K. J. Helton, and S. X. Skapek p18Ink4c and p53 Act as Tumor Suppressors in Cyclin D1-Driven Primitive Neuroectodermal Tumor Cancer Res., January 15, 2009; 69(2): 440 - 448. [Abstract] [Full Text] [PDF]

				J.-J. Lee, A. Y M Au, T. Foukakis, M. Barbaro, N. Kiss, R. Clifton-Bligh, J. Staaf, A. Borg, L. Delbridge, B. G Robinson, et al. Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma Endocr. Relat. Cancer, September 1, 2008; 15(3): 801 - 815. [Abstract] [Full Text] [PDF]

				N. Ogba, L. J. Chaplin, Y. Q. Doughman, K. Fujinaga, and M. M. Montano HEXIM1 Regulates 17{beta}-Estradiol/Estrogen Receptor-{alpha}-Mediated Expression of Cyclin D1 in Mammary Cells via Modulation of P-TEFb Cancer Res., September 1, 2008; 68(17): 7015 - 7024. [Abstract] [Full Text] [PDF]

				Y. Wang, J. L. Dean, E. K.A. Millar, T. H. Tran, C. M. McNeil, C. J. Burd, S. M. Henshall, F. E. Utama, A. Witkiewicz, H. Rui, et al. Cyclin D1b Is Aberrantly Regulated in Response to Therapeutic Challenge and Promotes Resistance to Estrogen Antagonists Cancer Res., July 15, 2008; 68(14): 5628 - 5638. [Abstract] [Full Text] [PDF]

				Y. Chen, L. Shi, L. Zhang, R. Li, J. Liang, W. Yu, L. Sun, X. Yang, Y. Wang, Y. Zhang, et al. The Molecular Mechanism Governing the Oncogenic Potential of SOX2 in Breast Cancer J. Biol. Chem., June 27, 2008; 283(26): 17969 - 17978. [Abstract] [Full Text] [PDF]

				R. A. Jones, C. I. Campbell, J. J. Petrik, and R. A. Moorehead Characterization of a Novel Primary Mammary Tumor Cell Line Reveals that Cyclin D1 Is Regulated by the Type I Insulin-Like Growth Factor Receptor Mol. Cancer Res., May 1, 2008; 6(5): 819 - 828. [Abstract] [Full Text] [PDF]

				M. Rudas, M. Lehnert, A. Huynh, R. Jakesz, C. Singer, S. Lax, W. Schippinger, O. Dietze, R. Greil, W. Stiglbauer, et al. Cyclin D1 Expression in Breast Cancer Patients Receiving Adjuvant Tamoxifen-Based Therapy Clin. Cancer Res., March 15, 2008; 14(6): 1767 - 1774. [Abstract] [Full Text] [PDF]

				J. X. Zou, A. S. Revenko, L. B. Li, A. T. Gemo, and H.-W. Chen ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ER{alpha}, is required for coregulator occupancy and chromatin modification PNAS, November 13, 2007; 104(46): 18067 - 18072. [Abstract] [Full Text] [PDF]

				Y. Li, Y. Zhang, J. Hill, Q. Shen, H.-T. Kim, X. Xu, S. G. Hilsenbeck, R. P. Bissonnette, W. W. Lamph, and P. H. Brown The Rexinoid LG100268 Prevents the Development of Preinvasive and Invasive Estrogen Receptor Negative Tumors in MMTV-erbB2 Mice Clin. Cancer Res., October 15, 2007; 13(20): 6224 - 6231. [Abstract] [Full Text] [PDF]

				Y. He, O. E. Franco, M. Jiang, K. Williams, H. D. Love, I. M. Coleman, P. S. Nelson, and S. W. Hayward Tissue-Specific Consequences of Cyclin D1 Overexpression in Prostate Cancer Progression Cancer Res., September 1, 2007; 67(17): 8188 - 8197. [Abstract] [Full Text] [PDF]

				H. Kikuchi, C. Uchida, T. Hattori, T. Isobe, Y. Hiramatsu, K. Kitagawa, T. Oda, H. Konno, and M. Kitagawa ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells Carcinogenesis, August 1, 2007; 28(8): 1752 - 1758. [Abstract] [Full Text] [PDF]

				E. Nurtjahja-Tjendraputra, D. Fu, J. M. Phang, and D. R. Richardson Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression Blood, May 1, 2007; 109(9): 4045 - 4054. [Abstract] [Full Text] [PDF]

				V. Boonyaratanakornkit, E. McGowan, L. Sherman, M. A. Mancini, B. J. Cheskis, and D. P. Edwards The Role of Extranuclear Signaling Actions of Progesterone Receptor in Mediating Progesterone Regulation of Gene Expression and the Cell Cycle Mol. Endocrinol., February 1, 2007; 21(2): 359 - 375. [Abstract] [Full Text] [PDF]

				M. A. Bewick, M. S.C. Conlon, and R. M. Lafrenie Polymorphisms in XRCC1, XRCC3, and CCND1 and Survival After Treatment for Metastatic Breast Cancer J. Clin. Oncol., December 20, 2006; 24(36): 5645 - 5651. [Abstract] [Full Text] [PDF]

				Z. Li, X. Jiao, C. Wang, X. Ju, Y. Lu, L. Yuan, M. P. Lisanti, S. Katiyar, and R. G. Pestell Cyclin D1 Induction of Cellular Migration Requires p27KIP1. Cancer Res., October 15, 2006; 66(20): 9986 - 9994. [Abstract] [Full Text] [PDF]

				J. Eeckhoute, J. S. Carroll, T. R. Geistlinger, M. I. Torres-Arzayus, and M. Brown A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer Genes & Dev., September 15, 2006; 20(18): 2513 - 2526. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, A. Articles by Papanikolaou, A. Search for Related Content PubMed PubMed Citation Articles by Arnold, A. Articles by Papanikolaou, A. Social Bookmarking                            What's this?