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20.1 INTRODUCTION

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Breast and prostate cancers are the most commonly occurring cancers in Western society, and are the second leading cause of cancer death (next to lung cancer) in women and men, respectively. Both of these cancers arise in tissues that require steroid sex hormones (estrogens and androgens) for their development, growth, and function. Although human cancers occur in other hormone-dependent tissues, such as the uterus, ovary, and testis, this chapter focuses exclusively on breast and prostate cancer as models of hormone-dependent cancers.

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The relationship between prostate enlargement and hormones produced by the testes has long been recognized. Although the chemical nature of androgens was not known, it was reported in 1895 that castration of elderly men with prostate enlargement, presumably as a result of benign prostatic hyperplasia, resulted in rapid atrophy of prostatic tissue. Early anecdotal evidence regarding the testicular (ie, androgen) dependence of the human prostate is also derived from studies involving eunuchs from the Ottoman and Chinese courts, which indicated that prostates did not develop in prepubertal castrates. Following the isolation of "testosterone" as the most potent androgenic compound in the testes in 1935, Huggins and Hodges demonstrated the efficacy of surgical orchiectomy for the treatment of metastatic prostate cancer, for which Huggins received the Nobel Prize for Medicine in 1966. Similarly, a link between estrogen and breast cancer growth was established at the end of the 19th century, when Beatson demonstrated that oophorectomy was useful in the treatment of metastatic breast cancer in some premenopausal women. However, a molecular basis for this observation was not forthcoming until the 1960s with the discovery of the estrogen receptor, followed by the demonstrated expression of estrogen receptors in some human breast tumors by Elwood Jensen.

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Evidence for a direct link between the action of sex steroids, and a causal role in the carcinogenic process leading to breast and prostate tumors, was first provided by Robert Noble. He reported that prolonged exposure to estrogen, androgen, or combinations of the 2 led to breast and prostate cancers in rats. More recently, the successful use of the antiestrogen, tamoxifen, to reduce the incidence of breast cancer in high-risk women, supports a direct link between estrogen action and breast tumor formation. These hormones are fundamental not only to the development of normal mammary and prostate glands, but also to dysplastic and neoplastic processes that occur in these tissues.

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In this chapter, relationships between hormones and cancers of the breast and prostate are explored in the context of basic mechanisms of hormone action, the natural history of the 2 diseases, and their treatment with hormonally based therapies.

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20.2 BASIC MECHANISMS OF HORMONE ACTION

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Hormones can be classified generally into 2 broad groups: (a) nonsteroidal (amino acids, peptides, and polypeptides), which usually require cell-membrane localized receptors that regulate second messenger molecules such as cyclic adenosine monophosphate (cAMP) to mediate their action (see ...

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