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A Century of Deciphering the Control Mechanisms of Sex Steroid Action in Breast and Prostate Cancer: The Origins of Targeted Therapy and Chemoprevention

Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: V. Craig Jordan, Medical Sciences, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497. Phone: 215-728-7410; Fax: 215-728-7034; E-mail: v.craig.jordan{at}fccc.edu.

Key Words: breast cancer • estrogen receptor • tamoxifen • antiestrogen • selective estrogen receptor modulators • selective androgen receptor modulator • antihormone • drug resistance • antiandrogens • prostate cancer

Abstract

The origins of the story to decipher the mechanisms that control the growth of sex hormone–dependent cancers started more than 100 years ago. Clinical observations of the apparently random responsiveness of breast cancer to endocrine ablation (hormonal withdrawal) provoked scientific inquiries in the laboratory that resulted in the development of effective strategies for targeting therapy to the estrogen receptor (ER; or androgen receptor in the case of prostate cancer), the development of antihormonal treatments that dramatically enhanced patient survival, and the first successful testing of agents to reduce the risk of developing any cancer. Most importantly, elucidating the receptor-mediated mechanisms of sex steroid–dependent growth and the clinical success of antihormones has had broad implication in medicinal chemistry with the synthesis of new selective hormone receptor modulators for numerous clinical applications. Indeed, the successful translational research on the ER was the catalyst for the current strategy for developing targeted therapies to the tumor and the start of "individualized medicine." During the past 50 years, ideas about the value of antihormones translated effectively from the laboratory to improve clinical care, improve national survival rates, and significantly reduced the burden of cancer. [Cancer Res 2009;69(4):1243–54]