Functions of dehydroepiandrosterone in relation to breast cancer

Highlights

• DHEA and DHEA sulfate (DS) are increased in HR positive breast cancer (BC)

• DHEA is not synthesized in mammary tissues but depends on transport of DS into cells.

• Progesterone, glucocorticoids and fatty acids modify organic anion transporters of DS.

• DHEA interacts with several membrane and cytosol receptors in the µmolar range.

• Androgen products of DHEA exert some activities but not all of those attributed to DHEA.

• Some metabolic products of DHEA have activities that greatly exceed those of DHEA.

• DHEA inhibits formation and activities of IL-6 and proinflammatory cytokines.

• DHEA stimulates the biosynthesis of IGF-I and inhibits that of IGFBP-1.

• The activity of DHEA will depend upon many factors in the cellular environment.

Abstract

Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of DS into cells requires organic anion transporting polypeptides (OATPs), which are specific for cell type, cell location, and substrate, but may have a broader specificity for housekeeping functions. Specific classes, which may be modified by soluble factors including neutral steroids, have been identified in the breast. After transport, DS may be cleaved to DHEA by ubiquitous sulfatases, which may be modified by the cell milieu, or DHEA may enter by diffusion. Synthesis from cholesterol does not occur because CYP17B12 and cytochrome b5 are lacking in breast tissues. Case-control studies reveal a positive association of serum DS with risk of breast cancer. The association is even greater with DHEA, particularly in postmenopausal women with HR + invasive tumors. Metabolites of DHEA, androstenedione and testosterone, are associated with breast cancer but DHEA is likely to have an independent role as well. Mechanisms by which DHEA may promote breast cancer relate to its effect in increasing circulating IGF-I, by inhibiting the suppressive effect of glucocorticoids, and by promoting retention of pre-adipocytes with aromatase activity. In addition, DHEA may interact with the G-protein coupled receptor GPER for stimulation of miR-21 and subsequent activation of the MAPK pathway. DHEA also has antitumor properties that relate to stimulation of immunity, suppression of inflammation, and elevation of adipose tissue adiponectin synthesis. The net effect may depend on the which factors predominate.

Introduction

Recently, we studied the association between hormone concentrations in nipple aspirate fluid (NAF) in unaffected contralateral breasts of cancer patients (N = 160), a high-risk site, and controls (N = 157). Among seven steroids tested, only DHEA was significantly greater in NAF of patients with breast cancer compared to control women: OR 1.19 (95% C.I. 1.04–1.36), P < 0.01. Further analysis showed that this was largely limited to women with ER-positive breast cancer. Serum DHEA was not significantly associated with risk, OR 0.95 (C.I. 0.66–1.35), P = 0.76, despite a significant correlation (r = 0.45) between NAF and serum DHEA concentrations. We wondered whether the increase in DHEA was related to an oncogenic process and whether the increased concentrations in women with high risk of breast cancer was caused by factors affecting uptake or metabolism of the high circulating levels of DHEA and its sulfate. We have reviewed case-control studies and more metabolic aspects to better understand the significance of DHEA in breast cancer.