Classification of breast cancer as endocrine sensitive, hormone dependent, or estrogen receptor (ER) positive refers singularly to ERα. One of the oldest recognized tumor targets, disruption of ERα-mediated signaling, is believed to be the mechanistic mode of action for all hormonal interventions used in treating this disease. Whereas ERα is widely accepted as the single most important predictive factor (for response to endocrine therapy), the presence of the receptor in tumor cells is also of prognostic value. Even though the clinical relevance of the two other sex hormone receptors, namely, ERβ and the androgen receptor remains unclear, two discordant phenomena observed in hormone-dependent breast cancers could be causally related to ERβ-mediated effects and androgenic actions. Nonetheless, our understanding of regulatory molecules and resistance mechanisms remains incomplete, further compromising our ability to develop novel therapeutic strategies that could improve disease outcomes. This review focuses on the receptor-mediated actions of the sex hormones in breast cancer. 1. Introduction Epidemiological, biological, and clinical data strongly implicate the role of sex hormones, primarily estrogens, in breast cancer; yet, their mere presence does not contribute to the malignant process. Inherent in this technically accurate paradox is that while the former supports the well-established link between estrogens, and possibly androgens, in this endocrine-related cancer, the latter infers that generation of the malignant phenotype requires other cellular components. Perhaps the most important “other” element is the hormone receptor. While the ligand/receptor construct is conceptually very simple, the molecular mechanisms by which sex hormones regulate a number of dynamic yet delicate processes in their target tissues are exceedingly more complex. The impetus for undertaking this endeavor was to merge our increased, though by no means complete, understanding of the estrogen and androgen receptors in breast cancer. As such, numerous published papers, some old but of enduring scientific value, were evaluated to support the conclusion that the nuclear steroid receptors are the essential link between hormone and disease. And to further enhance reader appreciation of this complex structure, the biology of the receptor is briefly reviewed in order to provide additional insight into the proposed mechanisms which promote tumor growth as well as facilitate tumor resistance. Here, the reader can learn a little about the treatment of hormone-dependent breast cancer,
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