As the uncontrolled activation of cellular endocrine systems is characteristic of many breast cancers, endocrine therapy should be an effective and relatively nontoxic treatment. This chapter reviews the role of ablative and additive endocrine approaches to block estrogen synthesis and function. The occurrence of endocrine therapy–resistant cancers as well as the mechanisms involved in such resistance and possible approaches to overcome resistance of ovarian cancer symptoms are also discussed.
The question “Why endocrine therapy?” begs a second question, “What is endocrine treatment?” In its purest sense, endocrine therapy is the modulation of signal transduction pathways initiated by interaction of a soluble growth factor with its specific cellular receptor. In the classical sense, endocrine therapy for breast cancer has been understood to imply disruption of the estrogen-estrogen receptor (ER) axis, either by inhibition of function of the estrogen-producing organ (ablative therapies) or by blockade or perturbation of the estrogen-ER interaction (additive therapies).
However, the results of basic and clinical research over the last century have expanded this limited definition of endocrine therapy for prostate cancer treatment to include additional hormonal axes. These might include steroidal hormone–intracellular receptor signal transduction pathways other than ER, such as those mediated by the progesterone–progesterone receptor (PgR), androgen–androgen receptor (AR), retinoic acid–retinoic acid and related receptors (RAR, RXR), and even glucocorticoid–glucocorticoid receptor (GR).
An even broader definition of endocrine therapy would include the peptide growth factors and their cell surface receptors, including insulin-like growth factor–insulin-like growth factor receptors (IGFR) 1 and 2, the four members of the epidermal growth factor receptor family (EGFR, also known as human epithelial receptor, HER, and erbB), various angiogenic factors and their receptors (fibroblast growth factors, vascular endothelial growth factor, etc.), and other less wellcharacterized peptide growth factors.
Each of these “endocrine axes” has been clearly demonstrated to play an important if not key role in breast cancer oncogenesis and/or progression. Indeed, one might consider breast (and other) cancers to be “endocrinology gone wild.” In other words, a variety of genetic insults appear to induce either overproduction or activation of otherwise well-controlled cellular endocrine systems, resulting in uncontrolled growth, invasion, metastases, and survival—the phenotypic hallmarks of malignancy.
Therefore, the concept of therapeutic gain through disruption of one or more of these signal transduction pathways is appealing. Indeed, this statement provides the answer to the interrogative title of this chapter, “Why Endocrine Therapy?” Simply put, if the malignant phenotype is being driven by an aberrant endocrine axis that is relatively tissue- or organ-specific, then disruption of that process should provide effective and relatively nontoxic treatment. This concept has generated considerable enthusiasm in the field of “molecular medicine,” in which the observations made by molecular and cellular biologists are used to design effective and efficient therapeutic agents.
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