Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

Abstract

Androgens play a critical role in the development and progression of prostate cancer (PCa), and androgen deprivation therapy via surgical or medical castration is front-line therapy for patients with advanced PCa. However, intratumoral testosterone levels are elevated in metastases from patients with castration-resistant disease, and residual intratumoral androgens have been implicated in mediating ligand-dependent mechanisms of androgen receptor activation. The source of residual tissue androgens present despite castration has not been fully elucidated, but proposed mechanisms include uptake and conversion of adrenal androgens, such as dehdroepiandrosterone to testosterone and dihydrotestosterone, or de novo androgen synthesis from cholesterol or progesterone precursors. In this minireview, we discuss the emerging evidence that suggests a role for specific transporters in mediating transport of steroids into or out of prostate cells, thereby influencing intratumoral androgen levels and PCa development and progression. We focus on the solute carrier and ATP binding cassette gene families, which have the most published data for a role in PCa-related steroid transport, and review the potential impact of genetic variation on steroid transport activity and PCa outcomes. Continued assessment of transport activity in PCa models and human tumor tissue is needed to better delineate the different roles these transporters play in physiologic and neoplastic settings, and in order to determine whether targeting the uptake of steroid substrates by specific transporters may be a clinically feasible therapeutic strategy. (Endocrinology 155: 4124 -4132, 2014)

Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer

“…(11) Characteristics of the specific SNPS in each gene and published associations with PCa are summarized in Supplementary Table S4. All SNPS were found to be in Hardy-Weinberg equilibrium (Supplementary Table S2).…”

The impact of statin use on the efficacy of abiraterone acetate in patients with castration‐resistant prostate cancer

“…If the mechanism is indeed mediated by SLCO transport, different SLCO SNPs may transport AA, DHEAS or statins with varying efficiency and potentially influence the clinical impact of concurrent AA and statin use . Adaptive increases in transport could result in more efficient use of residual non‐gonadal androgens . Similarly, Mostaghel et al have observed that serum DHEAS levels remain abundant in men despite treatment with AA leaving a circulating reservoir for tumor use …”

Mechanisms of drug resistance that target the androgen axis in castration resistant prostate cancer (CRPC)

“…For this conjugate to become bioavailable it must be transported by the solute carrier organic anion encoded membrane transporters (SLCO), also known as organic anion transporters (OATs). The members of this family involved in steroid uptake in the prostate include SLCO1A2 and SLCO2B1 [31]. The impact of SLCO genetic variation on steroid sequestration has been evaluated using SLCO2B1 variants in prostate cancer cells.…”