The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

Abstract

Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

“…Based on our data, BSP may also interfere with OATP1A2 and OATP1C1 function in vivo (serum concentrations can reach 3 µ m ); however, BSP is no longer used in liver function tests for humans . On the other hand, in vivo ES plasma concentrations are in the nanomolar range ; therefore, the in vivo relevance of OATP1A2 or OATP1C1 in ES transport may be less relevant. Similarly, the inhibitory effect of verapamil on OATP1A2 function may be negligible in vivo, since the maximal in vivo verapamil concentration is 0.21 µ m in contrast to the measured IC 50 of 7.18 µ m .…”

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

“…Drug development and potential therapeutic approaches are discussed. In this review, the enzymes involved in steroid deactivation/clearance (Rižner, 2013 , 2016 ; with the exclusion of steroid sulphotransferases) and those involved in the transport of conjugated steroids through the plasma membrane (Rižner et al, 2017 ) are not described. Studies on serum/tissue steroid levels are reported and discussed only if based on gold standard GC/LC-MS.…”

Influence of Chronic Neurogenic Pain on Local Levels of Sex Hormones and Receptors in Skin, Tumor and Perifocal Area in Male Mice With Transplantable В16/F10 Melanoma

“…Однако некоторые изоформы ERβ, такие как ERβ5, могут действовать и как онкоген [16]. Согласно гипотезе «несостоятельности эстрогенов», воздействие эндогенных или экзогенных эстрогенов в отсутствие действия андрогенов и прогестинов увеличивает пролиферацию и одновременные ошибки репликации ДНК, что приводит к соматическим мутациям и злокачественным трансформациям [1,17,18]. Подобные изменения могут быть одним из факторов, способствующих модификации злокачественного процесса, в частности у животных с хронической нейрогенной болью.…”

“…Стероидные гормоны играют важную роль в физиологии человека, а нарушение андрогенных, эстрогенных и прогестеронных воздействий связано с развитием различных видов как злокачественных, так и доброкачественных пролиферативных заболеваний [1]. Установлена важная роль локального синтеза половых стероидов за счет наличия ферментов CYP11A1 и CYP17A1 в периферических тканях, что дает возможность автономной регуляции пролиферативных процессов, включая доброкачественные и злокачественные опухоли [2].…”