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Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy

From the Breast Center, Baylor College of Medicine; and the Methodist Hospital, Houston, TX

Address reprint requests to Adrian V. Lee, PhD, Breast Center, Baylor College of Medicine, Houston, TX 77030; e-mail: avlee{at}breastcenter.tmc.edu

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

Supported by National Institutes of Health grant Nos. CA94118 (A.V.L.), P50 CA58183 (C.K.O.), and P01 CA30195 (C.K.O.), and the Department of Defense Postdoctoral Fellowship Award DAMD17-01-1-0133 (X.C.).

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

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