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© 1999 American Society for Clinical Oncology Expression of BAG-1 in Invasive Breast CarcinomasFrom the Departments of Medicine and Pathology, the Division of Community Healthy, and Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, and Newfoundland Cancer Treatment and Research Foundation, Dr H. Bliss Murphy Cancer Centre, St. John's, Newfoundland, Canada. Address reprint requests to Shou-Ching Tang, MD, PhD, Newfoundland Cancer Treatment and Research Foundation, Dr H. Bliss Murphy Cancer Centre, 300 Prince Philip Dr, St. John's, NF, Canada A1B 3V6; email stang{at}nctrf.nf.ca
PURPOSE: The purpose of this study was to retrospectively evaluate the expression of BAG-1 in invasive breast carcinomas. The intensity and subcellular distribution of BAG-1 expression was correlated with conventional prognostic factors and with disease-free and overall survival. PATIENTS AND METHODS: One hundred forty patients diagnosed with invasive breast cancer in St. John's, Newfoundland, between 1986 and 1996 were included in the study. The median follow-up of the study was 8 years. Expression of BAG-1 was determined by immunohistochemical staining of paraffin-embedded breast tumor tissues. RESULTS: Of the 140 breast carcinomas examined, 77.1% were positive for BAG-1 expression. Except for differentiation, no correlation was observed between BAG-1 expression and conventional prognostic factors such as age, histology, stage, and estrogen and progesterone receptor status. In multivariate analysis, BAG-1 expression was significantly associated with shorter disease-free (P = .0052) and overall survival (P = .0033). Patients whose tumors expressed nuclear BAG-1 tended to have a shorter disease-free (63 v 84 months; P = 0.4493) and overall (69 v 99 months, P = .1009) survival. CONCLUSION: BAG-1 is overexpressed in the majority of invasive breast carcinomas. Although BAG-1 did not correlate with conventional prognostic factors, its overexpression, especially the nuclear expression, may be associated with a shorter disease-free and overall survival. Our preliminary data strongly indicate that further investigation is warranted to define the role of BAG-1 as an independent prognostic factor in patients with newly diagnosed breast cancer.
BREAST CANCER IS the most common malignancy affecting women. One of the most important issues facing clinicians in the evaluation of breast cancer is how to predict the aggressiveness of small invasive breast carcinomas. Commonly used prognostic factors such as tumor size, grade, nodal status, and hormonal receptors are of limited value. Additional biologic prognostic parameters are needed to help the clinician to identify patients who have more aggressive disease and to offer appropriate treatment. In the last two decades, factors such as proliferative activities, oncogene amplification, inactivation of tumor suppressor genes, and activation of growth factor receptors have been studied for their utilization in clinical practice. However, their true clinical value remains to be determined. Recently, a new category of genes that control the process of programmed cell death or apoptosis has been identified. This includes the antiapoptotic proto-oncogene, Bcl-2, and the proapoptotic genes, bax and p53. Increased apoptotic index was associated with high tumor grade, large tumor size, DNA aneuploidy, high S phase, high mitotic rate, lack of estrogen receptor (ER), and shorter disease-free and overall survival.1 Increased expression of Bcl-2 was found in the majority of breast cancer cases. Its expression was correlated with the presence of ERs, progesterone receptors, (PRs) and well-differentiated tumor; its expression was inversely correlated with p53 expression and the apoptotic index.2-5 Furthermore, the expression of Bcl-2 was associated with the absence of lymph node metastases, better response to hormonal therapy, and longer disease-free and overall survival in breast cancer patients.6-13 However, the expression of Bcl-x, a Bcl-2–related antiapoptotic protein, was shown to be associated with decreased overall survival in breast cancer patients.14 In addition, reduced expression of BAX, the proapoptotic Bcl-2 analog, is associated with poor response to combination chemotherapy and a shorter survival of patients with invasive breast cancer.15 Increased expression of mutant p53, a proapoptotic tumor suppressor gene, is associated with resistance to chemotherapy or radiation therapy and shorter disease-free and overall survival.16-18 Taken together, these data strongly suggest that apoptosis plays an important role in the pathogenesis and progression of breast cancer, although the use of apoptosis molecules as independent prognostic factors in breast cancer patients is still controversial. This is largely due to the current poor understanding of Bcl-2 expression and its interaction with other apoptotic gene products. Indeed, our previous studies on diffuse large-cell non-Hodgkin's lymphoma revealed that the expression of Bcl-2 protein did not correlate with Bcl-2 gene rearrangements.19 Our observation reinforces the need to study other Bcl-2–interacting proteins in order to fully assess the biologic significance and prognostic value of Bcl-2 in breast cancer patients. BAG-1 is a recently identified Bcl-2–binding antiapoptotic protein that may play an important role in the pathogenesis of breast cancer. BAG-1 was shown to interact with Bcl-2 and enhanced the antiapoptotic activity of Bcl-2 in in vitro experiments.20 It also binds to hepatocyte growth factor receptor and enhances the protection from apoptosis by hepatocyte growth factor receptor.21 Overexpression of BAG-1 resulted in sustained cell viability and proliferation, with minimal apoptosis and a growth factor–independent state.22,23 In addition, a synergistic antiapoptotic effect was noted when Bcl-2 and BAG-1 were cotransfected.20,24 Furthermore, transfer-mediated expression of BAG-1 in melanoma cells led to enhanced pulmonary metastasis compared with that of the control transfectants.25 More significantly, BAG-1 was able to bind to nuclear hormone receptors (such as ER) and inhibit corticosteroid-induced apoptosis.26,27 BAG-1 also binds to androgen receptor and enhances its transactivation function.28 We have newly observed that the human BAG-1/RAP46 proteins are generated as four isoforms by alternative translation initiation and are expressed as either nuclear or cytoplasmic proteins in tumor cell lines.29 Increased BAG-1 expression has been noted in breast cancer cell lines and breast cancer tumors, and its expression was correlated with that of Bcl-2 proteins.30,31 The exact mechanism by which BAG-1 cooperates with Bcl-2 to suppress apoptosis is currently unknown. BAG-1 may exert its function through modulation of chaperone activity of the 70-kda heat shock protein (Hsc70).32,33 Current literature indicates that BAG-1 interacts with growth factor receptors, Hsc70, and Bcl-2 to suppress apoptosis. BAG-1 also binds to hormone receptors (such as ER) and suppresses hormone-induced apoptosis. Our hypothesis is that abnormal BAG-1 expression plays an important role in the pathogenesis and progression of breast cancer. Furthermore, abnormal expression of BAG-1 may be used as a prognostic factor in guiding clinical management of invasive breast cancer. To test our hypothesis, we conducted the first large-scale retrospective study of BAG-1 expression in 140 breast carcinomas, using immunohistochemical staining of paraffin-embedded breast cancer samples. The median patient follow-up was 8 years. BAG-1 expression was analyzed in conjunction with conventional prognostic factors, such as tumor size, histology, grade, receptor status, stage, and disease-free and overall survival. Our results indicated that BAG-1 was overexpressed in the majority of breast cancer tissues. Furthermore, the study demonstrated that the expression of BAG-1 varies from patient to patient. More significantly, we detected two patterns of BAG-1 expression in breast cancer, cytoplasmic and nuclear. We have correlated the presence or absence of BAG-1 expression, its staining intensity, and its subcellular localization with the conventional prognostic factors. The use of BAG-1 expression as a prognostic factor in guiding clinical treatment of invasive breast cancer will be discussed.
Patient Inclusion and Exclusion All patients diagnosed with invasive breast cancers in the St. John's area (Health Sciences Centre and St. Clare's Hospital) between 1986 and 1996 were included, with the following exceptions: patients without paraffin-embedded tissue, patients who were lost to follow-up, and all male patients were excluded. Patients were observed from the time of diagnosis to December 1997 or until the time of death. The diagnosis of breast cancer was based on frozen and paraffin-embedded tissue sections. Histology and tumor grade were independently confirmed by a second pathologist.
BAG-1 Expression by Immunohistochemistry
Statistical Analysis
Patient Population One hundred forty patients were included in the study as listed in Table 1. The age range was 30 to 96 years, with a mean and median age of 61.19 and 63 years, respectively. Three patients were missing dates of birth. One hundred twenty-four patients (88.6%) were diagnosed with infiltrating ductal carcinoma, 10 patients were diagnosed with infiltrating lobular carcinoma (7.1%), and six patients (4.3%) were diagnosed with mucinous and medullary carcinomas. Fifty-nine patients (42.1%) had well-differentiated tumors, 29 patients (20.7%) had moderately differentiated tumors, and 29 patients (20.7%) were diagnosed with high-grade, poorly differentiated tumors. Twenty-three patients (16.5%) were missing initial tumor grade diagnoses. Forty-nine patients (35.0%) had ER-positive tumors, 12 patients (8.6%) had ER-negative tumors, 26 patients (18.6%) had ER-equivocal tumors, and 53 patients (37.8%) had unknown ER status. Forty-five patients (32.1%) had PR-positive tumors, 17 patients (21.1%) had PR-negative tumors, 24 patients (17.1%) had PR-equivocal tumors, and 54 patients (38.7%) had unknown PR status. Thirty patients (21.4%) had stage I disease, 61 patients (43.6%) had stage II disease, 11 patients (7.9%) had stage III disease, and 16 patients (11.4%) had stage IV disease. Staging information could not be verified for 22 patients (15.7%). Fifty-four patients (38.6%) received single-modality radiation therapy, chemotherapy, or hormonal therapy; 18 patients (12.9%) received no therapy; 29 patients (19.3%) received a combined-modality treatment. Treatment information could not be obtained in 41 patients (29.2%). The minimal patient follow-up was 1 month and the maximum was 10 years, with a mean and median follow-up of 6.5 and 8 years, respectively. At the time of analysis, 58 patients (40.6%) were alive and disease-free, six patients (4.2%) were alive with recurrence, seven patients (4.9%) were diseased without recurrence, 30 patients (21.0%) were diseased due to recurrence, eight patients (5.6%) experienced disease recurrence but died of other causes, six patients (4.2%) experienced disease recurrence but died of unknown causes, seven patients (4.9%) had no disease recurrence (although their survival data was unknown), and 21 patients (14.7%) were lost to follow-up after initiatial diagnosis. The cumulative disease-free and overall survival of the patient population are summarized in Fig 1. The 1-year, 2-year, and 5-year disease-free and overall survival rates of this patient population were 76.2%, 47.5%, and 28.7% (disease-free), and 81.3%, 58.5%, and 33.3% (overall), respectively.
BAG-1 Expression
Except for differentiation, no correlations were observed between BAG-1 expression and conventional prognostic factors such as age (P = .707), histology (P = .623), stage (P = .569), ER (P = .243), and PR (P = .174) by Spearman correlation coefficient. Similarly, the pattern of BAG-1 staining (cytoplastic v nuclear) did not correlate with age (P = .547), histology (P = .464), stage (P = .860), ER (P = .924), and PR (P = .911), as listed in Table 2. BAG-1 expression, especially nuclear BAG-1 expression, was associated with well-differentiated breast tumors (P = .025 and P = .022, respectively). When examined in a univariate analysis, BAG-1 expression did not correlate with either disease-free (P = .2369) or overall survival (P = .2848). Similarly, the pattern of BAG-1 expression did not correlate with disease-free (P = .4493) or overall survival (P = .1009). However, BAG-1 expression (P = .0052 and P = .0033) and stage (P = .0000 and P = .0001) were significantly correlated with shorter disease-free and overall survival in the multivariate analysis, as listed in Table 3. Although the degree of differentiation was significantly associated with a shorter disease-free survival (P = .0070), its association with overall survival was not significant (P = .3334). ER and PR status were not included in the multivariate analysis due to the high number of missing values (37.9% and 38.6%, respectively). Furthermore, from Kaplan-Meier analysis and log-rank tests, patients whose tumors expressed BAG-1 tended to have shorter disease-free (71 v 84 months; P = .2369) and overall (89 v 99 months; P = .2848) survival, although the difference did not reach statistical significance. Similarly, patients whose tumors expressed nuclear BAG-1 tended to have a shorter disease-free (63 v 84 months, P = .4493) and overall (69 v 99 months; P = .1009) survival. The correlation between BAG-1 expression and its distribution pattern and patient survival are illustrated in Figs 3 and 4, respectively.
We also analyzed the correlation between the intensity of BAG-1 expression and survival. Univariate analysis found no correlation between the intensity of BAG-1 expression and disease-free (P = .6251) and overall (P = .4928) survival (Fig 5). When BAG-1 expression was analyzed within stage, the strongest prognostic factor in breast cancer prognosis, patients whose tumors expressed BAG-1 exhibited a trend toward shorter disease-free and overall survival for stage I (P = .2700 and P = .40207, respectively), stage II (P = .1620 and P = .1995, respectively), stage III (P = .0631 and P = .1787, respectively), and stage IV (P = .1349 and P = .1934, respectively), although the difference was not statistically significant, as illustrated in Table 4.
Discussion This is the first large-scale retrospective study to assess the clinical significance of BAG-1 expression in invasive breast carcinomas. The pattern and intensity of BAG-1 staining were correlated with conventional prognostic factors such as tumor size, grade, histology, receptor status, and stage. In addition, disease-free and overall survival of patients whose tumors expressed BAG-1 were analyzed. Our study shows that 77.1% of breast carcinomas overexpressed BAG-1 in varying amounts. In addition, 57.1% of BAG-1 overexpression was observed in cytoplasm, whereas 18.6% was observed in the nucleus. Except for differentiation, the degree or pattern of BAG-1 expression did not correlate with age, histology, receptor status, and stage. This is in sharp contrast with Bcl-2, which is positively correlated with better differentiation, positive receptor status, and lower stage. Although the expression of BAG-1 and Bcl-2 is positively correlated,31 this correlation was observed using only a few breast cancer cell lines and three primary breast tumors. In addition, BAG-1 and Bcl-2 may play different roles in breast cancer oncogenesis. Indeed, BAG-1, not Bcl-2, binds to ER and inhibits estrogen-induced apoptosis.26,27 Our observation of the overexpression of BAG-1 in the majority of breast carcinomas suggests that BAG-1 plays an important role in the pathogenesis of breast cancer, although its function may be independent of Bcl-2 expression. It would be interesting to further analyze the coexpression of Bcl-2 and BAG-1 in a larger retrospective or prospective study. Although BAG-1 binds to ER and may affect estrogen-induced apoptosis, our study showed no correlation between the expression of the two proteins. This indicates that the apoptosis mediated by ER is regulated by additional factors, and is not solely dependent on the expression of BAG-1 protein. Other factors, such as Hsp70, may be involved in mediating BAG-1/ER-regulated apoptosis. Because the majority of breast cancers express BAG-1 and there is no correlation between its expression and conventional prognostic factors, BAG-1 may serve as an independent predictive factor in breast cancer prognosis. The follow-up of our patient population is long, with a mean of 6.5 years and a median of 8 years. Although BAG-1 expression did not correlate with the survival of patients in univariate analysis, its expression was significantly associated with disease-free and overall survival in our multivariate analysis. More importantly, the significant association between BAG-1 expression and overall survival persisted even when differentiation was no longer significant. Differentiation was the only conventional prognostic factor that was positively linked to BAG-1 expression. Furthermore, our study indicates that patients whose tumors expressed BAG-1 tended to have shorter disease-free and overall survival. Similarly, patients whose tumors expressed nuclear BAG-1 tended to have shorter disease-free and overall survival, although the differences did not reach statistical significance. Although no correlation of BAG-1 staining intensity with either disease-free or overall survival was noted, subgroup analyses consistently revealed a trend toward less favorable outcome in patients in all stages of breast cancer whose tumors expressed BAG-1. Our observation that patients whose tumors expressed BAG-1 tended to have less favorable clinical outcome is interesting, because the BAG-1–interacting Bcl-2 has been shown to be linked to a more favorable outcome. In a recent Southwest Oncology Group study, increased Bcl-2 expression remained significantly associated with a longer disease-free and overall survival when ER, PR, and p53 were included in the multivariant analysis.34 The association of Bcl-2 with a favorable clinical outcome in breast cancer patients was further supported in another large retrospective study that involved 979 patients with positive axillary lymph nodes.35 Because the antiapoptotic effect of BAG-1 depends on the presence of Bcl-2,20 overexpression of BAG-1 without the concomitant increase of Bcl-2 may result in deregulation of apoptosis of breast cancer cells, hence worsening prognosis. The mechanism by which BAG-1 interacts with Bcl-2 to suppress apoptosis is still poorly understood. Many conflicting reports demonstrate that increased expression of Bcl-2 may not always predict a favorable clinical outcome. In the multivariate analysis involving 283 node-negative breast cancer patients, Bcl-2 failed to maintain its prognostic role for relapse-free and overall survival.36 The lack of prognostic value of Bcl-2 expression was also noted in both node-positive and node-negative patients.37,38 In fact, it was observed that increased Bcl-2 expression was associated with lymph node metastases and tumor progression in breast cancer patients.39,40 Although our study included 140 invasive breast carcinomas, the power to detect real differences in disease-free and overall survival is still low because of the heterogeneous population of patients with different tumors, grades, stages, receptor statuses, and treatments. A larger retrospective study is underway to assess the expression of BAG-1 together with Bcl-2 and p53 in breast carcinomas. In addition, prospective studies using fresh tissue, as well as paraffin-embedded samples, would further quantitate the degree of BAG-1 expression in relation to other pro- and antiapoptotic molecules and to correlate its expression with patient survival. Equally important is our observation that patients whose tumors expressed nuclear BAG-1 tended to have a less favorable clinical outcome compared with that of patients whose tumors expressed cytoplasmic BAG-1. Because BAG-1 binds to nuclear hormone receptors such as ER and affects their transactivation function,27,28 overexpression of nuclear BAG-1 would be more functionally significant. Our correlative study of breast carcinomas seems to support this hypothesis. Experiments are underway to study the functional difference between the 50-kda and 46-kda BAG-1 isoforms that are distributed in the nucleus and cytoplasm of tumor cells, respectively. Our study established for the first time that BAG-1 is overexpressed in a majority of breast carcinomas and that its expression varies from patient to patient. Furthermore, we observed two patterns of BAG-1 distribution: cytoplasmic and nuclear. The wide expression of BAG-1 suggests that it plays an important role in the pathogenesis of breast cancer. More importantly, our study indicates that patients whose tumors overexpress BAG-1, especially nuclear BAG-1, may have a shorter survival, and therefore, such patients may require more aggressive treatment. Our study strongly indicates that further large-scale retrospective and prospective studies are warranted to test the value of BAG-1 expression in guiding the clinical management of invasive breast cancers.
Supported by grants from the Newfoundland Cancer Treatment and Research Foundation, Memorial University of Newfoundland, the Medical Research Council of Canada, and the National Cancer Institute of Canada
1. Lipponen P, Aaltomaa S, Kosma VM, et al: Apoptosis in breast cancer as related to histopathological characteristics and prognosis. Eur J Cancer 30A:2068-2073, 1994
2.
Nathan B, Gusterson B, Jadayel D, et al: Expression of BCL-2 in primary breast cancer and its correlation with tumour phenotype. Ann Oncol 5:409-414, 1994 3. Bhargava V, Kell DL, van de Rijn M, et al: Bcl-2 immunoreactivity in breast carcinoma correlates with hormone receptor positivity. Ann J Pathol 145:535-540, 1994 4. Gee JMW, Robertson JFR, Ellis IO, et al: Immunocytochemical localization of Bcl-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. Int J Cancer 59:619-628, 1994[Medline] 5. Hori M, Nogami T, Itabashi M, et al: Expression of Bcl-2 in human breast cancer: Correlation between hormone receptor status, p53 protein accumulation and DNA strand breaks associated with apoptosis. Pathol Int 47:757-762, 1997[Medline] 6. Joensuu H, Pylkkänen L, Toikkanen S: Bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198, 1994
7.
Ceccarelli C, Santini D, Chieco P, et al: Multiple expression patterns of biopathological markers in primary invasive breast carcinoma: A useful tool for elucidating its biological behaviour. Annals of Oncol 6:275-282, 1995 8. Lipponen P, Pietilainen T, Kosma VM, et al: Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis. J Pathol 177:49-55, 1995[Medline] 9. Barbareschi M, Caffo O, Veronese S, et al: Bcl-2 and p53 expression in node-negative breast carcinoma: A study with long-term follow-up. Human Pathol 27:1149-1155, 1996[Medline] 10. Visscher DW, Sarkar F, Tabaczka P, et al: Clinicopathologic analysis of bcl-2 immunostaining in breast carcinoma. Mod Pathol 9:642-646, 1996[Medline] 11. Sundlad AS, Ahn C, Battifora A: Immunohistochemical detection of bcl-2 and MIB-1/Ki-67 in breast cancer: Retrospective analysis of 238 cases. Medicina (B Aires) 56:252-258, 1996[Medline] 12. Kobayashi S, Iwase H, Ito Y, et al: Clinical significance of bcl-2 gene expression in human breast cancer tissues. Breast Cancer Res Treat 42:173-181, 1997[Medline] 13. Kapranos N, Karaiosifidi H, Valavanis C, et al: Prognostic significance of apoptosis related proteins Bcl-2 and Bax in node-negative breast cancer patients. Anticancer Res 17:2499-2505, 1997[Medline] 14. Olopade OI, Adeyanju MO, Safa AR, et al: Over-expression of BCL-x protein in primary breast cancer is associated with high tumor grade and nodal metastases. Cancer J Sci Am 3:230-237, 1997[Medline]
15.
Krajewski S, Blomqvist C, Franssila K, et al: Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res 55:4471-4478, 1995 16. Aas T, Borresen AL, Geisler S, et al: Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2:811-814, 1996[Medline] 17. Linn SC, Honkoop AH, Hoekman K, et al: p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. Br J Cancer 74:63-68, 1996[Medline] 18. Degeorges A, de Roquancourt A, Extra JM, et al: Is p53 a protein that predicts the response to chemotherapy in node negative breast cancer? Breast Cancer Res Treat 47:47-55, 1998[Medline] 19. Tang S-C, Visser L, Hepperle B, et al: Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin's lymphoma: An analysis of 83 cases. J Clin Oncol 12:149-154, 1994[Abstract] 20. Takayama S, Sato T, Krajewski S, et al: Cloning and functional analysis of BAG-1: A novel Bcl-2 binding protein with anti-cell death activity. Cell 80:279-284, 1995[Medline] 21. Bardelli A, Longati P, Albero D, et al: HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO J 15:6205-6212, 1996[Medline]
22.
Clevenger CV, Thickman K, Ngo W, et al: Role of Bag-1 in the survival and proliferation of the cytokine-dependent lymphocyte lines, Ba/F3 and Nb2. Mol Endocrinol 11:608-618, 1997 23. Sekiya M, Adachi M, Takayams S, et al: IFN-gamma upregulates anti-apoptotic gene expression and inhibits apoptosis in IL-3-dependent hematopoietic cells. Biochem Biophys Res Commun 239:401-406, 1997[Medline] 24. Terada S, Fukuoka K, Fujita T, et al: Anti-apoptotic genes, bag-1 and bcl-2, enabled hybridoma cells to survive under treatment for arresting cell cycle. Cytotechnology 25:17-23, 1997[Medline] 25. Takaoka A, Adachi M, Okuda H, et al: Anti-cell death activity promotes pulmonary metastasis of melanoma cells. Oncogene 14:2971-2977, 1997[Medline]
26.
Zeinet M, Gehring U: A protein that interacts with members of the nuclear hormone receptor family: Identification and cDNA cloning. Proc Natl Acad Sci U S A 92:11465-11469, 1995
27.
Kullmann M, Schneikert J, Moll J, et al: RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis. J Biol Chem 273:14620-14625, 1998
28.
Froesch BA, Takayama S, Reed JC: BAG-1L protein enhances androgen receptor function. J Biol Chem 273:11660-11666, 1998 29. Yang X, Chernenko G, Hao Y, et al: Human BAG-1/RAP46 proteins are generated as four isoforms by alternative translation initiation and overexpressed in human cancer cells. Oncogene 17:981-989, 1998[Medline] 30. Yang X, Hao Y, Pater A, et al: Differential expression of anti-apoptotic gene BAG-1 in human breast normal and cancer cell lines and tissues. Clin Cancer Res (in press) 31. Zapata JM, Krajewska M, Krajewski S, et al: Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumours. Breast Cancer Res Treat 47:129-140, 1998[Medline] 32. Höhfeld J, Jentsch S: GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16:6209-6216, 1997[Medline] 33. Takayama S, Bimston DN, Matsuzawa S, et al: BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J 16:4887-4896, 1997[Medline]
34.
Elledge RM, Green S, Howes L, et al: Bcl-2, p53 and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: A Southwest Oncology Group study. J Clin Oncol 15:1916-1922, 1997 35. Berarda MD, Elledge RM, de Moor C, et al: Bcl-2 and apoptosis in lymph node positive breast carcinoma. Cancer 82:1296-1302, 1998[Medline]
36.
Silvestrini R, Veneroni S, Daidone MG, et al: The Bcl-2 protein: A prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst 86:499-504, 1994 37. Hellemans P, van Dam PA, Weyler J, et al: Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 72:354-360, 1995[Medline] 38. Papadimitriou CS, Costopoulos JS, Christoforidou BP, et al: Expression of Bcl-2 protein in human primary breast carcinomas and its correlation with multifocality, histopathological types and prognosis. Eur J Cancer 33:1275-1280, 1997 39. Sierra A, Lloveras B, Castellsague X, et al: Bcl-2 expression is associated with lymph node metastasis in human ductal breast carcinoma. Int J Cancer 60:54-60, 1995[Medline] 40. Gorczyca W, Markiewski M, Kram A, et al: Innumohistochemical analysis of bcl-2 and p53 expression in breast carcinomas: Their correlation with Ki-67 growth fraction. Virchows Arch 426:229-233, 1995[Medline] Submitted August 28, 1998; accepted February 1, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
