Evolving Understanding of Growth Regulation in Human Breast Cancer: Interactions of the Steroid and Peptide Growth Regulatory Pathways

Abstract

Ablation of systemic estrogen production in a breast cancer patient is considered to be one of the fi rst targeted therapies employed for the treatment of a human malignancy. Since Beatson’s ( 1 ) initial clinical description of a breast tumor response to oophorectomy in 1896, many approaches that disrupt the estrogen – estrogen receptor (ER) signaling pathway have been developed and used widely in clinical practice. These range from surgical approaches such as oophorectomy, adrenalectomy, and hypophysectomy to the use of highly refi ned antagonists of the ER and agents that directly target estrogen production, such as aromatase inhibitors. The routine measurement of ER in breast cancers and the relative restriction of hormonally directed therapies to patients with ER-positive tumors has led to a more rational and appropriate use of these modalities. These antiendocrine interventions have had a clinically signifi cant benefi t for many patients with advanced disease. Moreover, these approaches have made a substantial impact on clinical outcomes when used in the adjuvant setting, and some agents (like tamoxifen) have also shown effi cacy when used as part of prevention strategies. Unfortunately, for many patients, the initial clinical benefi ts are followed by the development of recurrent disease that either does not respond or responds minimally to further manipulation of the estrogen signaling pathway. Other patients display de novo rather than acquired resistance, despite having ER-positive tumors. This antihormone resistance or hormone-independent phenotype has been the subject of intense study for more than 40 years, and many hypotheses have been put forward to address its molecular basis. Proposed resistance mechanisms range from alterations (i.e., mutation, overexpression, or gene amplifi cation) in the ER target to mechanisms that inactivate the therapeutic drug itself. Although these studies have provided some interesting insights, none of these hypotheses has explained the molecular basis of resistance in most nonresponsive human breast cancers. Since the identifi cation of the progesterone receptor (PR) as a downstream target of the liganded ER and the subsequent development of techniques to routinely measure PR levels in breast cancer specimens, data have accumulated indicating that ER-positive/ PR-negative (ER + /PR − ) tumors are less responsive than ER + /PR + tumors to therapeutics directed at the ER. This fi nding led many to postulate that a major mechanism of resistance to estrogen/ERdirected treatments was an altered or “ nonfunctioning ” ER signaling pathway and that a lack of PR expression was a refl ection of this loss of activity. This hypothesis has held prominence for many years until, in part, the publication of recent clinical trials demonstrating that ER + /PR + and ER + /PR − tumors respond similarly to an aromatase inhibitor that decreases systemic and/or local tissue estrogen levels ( 2 ) . These data suggest that the ER pathway is functional in many ER + /PR − breast cancers.