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.

Figure 1.

Steroid hormones, such as estrone-sulfate (circles labeled E), dihydroepiandrosterone-sulfate (DHEA-S, circles labeled D), pregnenolone (circles labeled P), and T (circles labeled T), can be transported into cancer cells by transporters, such as the SLCO/OATP family proteins and/or Megalin. Presence of the appropriate intracellular enzymes may allow conversion of these hormones into estradiol (E2), DHEA, T, and DHT. E2 and DHT can bind to estrogen receptor (ER) and AR, respectively, which homo-dimerize and enter the nucleus to influence transcription of genes that enhance growth and survival. DHEA can activate AR bearing certain mutations in the ligand binding domain. Steroid hormones can also be metabolized by enzymes, and the hormones and metabolites can be actively effluxed through the ABC-transporter family. Polymorphisms or differential expression of these transporters can impact the influx and efflux of steroid hormones, which may in turn affect the balance of intratumoral steroids and overall tumor growth.