Adrenal Steroids and Resistance to Hormonal Blockade of Prostate and Breast Cancer

Abstract

Abstract Prostate cancer and breast cancer are sex-steroid–dependent diseases that are driven in major part by gonadal sex steroids. Testosterone (T) is converted to 5α-dihydrotestosterone, both of which stimulate the androgen receptor (AR) and prostate cancer progression. Estradiol is the major stimulus for estrogen receptor-α (ERα) and proliferation of ERα-expressing breast cancer. However, the human adrenal provides an alternative source for sex steroids. A number of different androgens are produced by the adrenals, the most abundant of which is dehydroepiandrosterone (DHEA) and DHEA sulfate. These precursor steroids are subject to metabolism by peripherally expressed enzymes that are responsible for the synthesis of potent androgens and estrogens. In the case of prostate cancer, the regulation of one of these enzymatic steps occurs at least in part by way of a germline-encoded missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which regulates potent androgen biosynthesis and clinical outcomes in men with advanced prostate cancer treated with gonadal T deprivation. The sex steroids that drive prostate cancer and breast cancer require a common set of enzymes for their generation. However, the pathways diverge once 3-keto, Δ4-androgens are generated and these steroids are either turned into potent androgens by steroid-5α-reductase, or into estrogens by aromatase. Alternative steroid receptors have also emerged as disease- and treatment-resistance modifiers, including a role for AR in breast cancer and glucocorticoid receptor both in breast and prostate cancer. In this review, we integrate the commonalities of adrenal steroid physiology that regulate both prostate and breast cancer while recognizing the clear distinctions between these diseases.