Estrone-3-Sulfate Stimulates the Proliferation of T47D Breast Cancer Cells Stably Transfected With the Sodium-Dependent Organic Anion Transporter SOAT (SLC10A6)

Abstract

Estrogens play a pivotal role in the development and proliferation of hormone-dependent breast cancer. Apart from free estrogens, which can directly activate the estrogen receptor (ER) of tumor cells, sulfo-conjugated steroids, which maintain high plasma concentrations even after menopause, first have to be imported into tumor cells by carrier-mediated uptake and then can be cleaved by the steroid sulfatase to finally activate ERs and cell proliferation. In the present study, expression of the sodium-dependent organic anion transporter SOAT was analyzed in breast cancer and its role for hormone-dependent proliferation of T47D breast cancer cells was elucidated. The SOAT protein was localized to the ductal epithelium of the mammary gland by immunohistochemistry. SOAT showed high expression in different pathologies of the breast with a clear ductal localization, including ductal hyperplasia, intraductal papilloma, and intraductal carcinoma. In a larger breast cancer cDNA array, SOAT mRNA expression was high in almost all adenocarcinoma specimen, but expression did not correlate with either the ER, progesterone receptor, or human epidermal growth factor receptor 2 status. Furthermore, SOAT expression did not correlate with tumor stage or grade, indicating widespread SOAT expression in breast cancer. To analyze the role of SOAT for breast cancer cell proliferation, T47D cells were stably transfected with SOAT and incubated under increasing concentrations of estrone-3-sulfate (E1S) and estradiol at physiologically relevant concentrations. Cell proliferation was significantly increased by 10-9 M estradiol as well as by E1S with EC50 of 2.2 nM. In contrast, T47D control cells showed 10-fold lower sensitivity to E1S stimulation with EC50 of 21.7 nM. The E1S-stimulated proliferation of SOAT-T47D cells was blocked by the SOAT inhibitor 4-sulfooxymethylpyrene. In conclusion: The present study clearly demonstrates expression of SOAT in breast cancer tissue with ductal localization. SOAT inhibition can block the E1S-stimulated proliferation of T47D breast cancer cells, demonstrating that SOAT is an interesting novel drug target from the group of E1S uptake carriers for anti-proliferative breast cancer therapy.

The cell cycle‐related genes RHAMM, AURKA, TPX2, PLK1, and PLK4 are associated with the poor prognosis of breast cancer patients

“…It has been described that the expression of the ER promotes the proliferation of the luminal cells lines MCF-7 and T47D. 108,109 This could explain why these cells have the higher expression of the cell cycle-related genes. Also, luminal cells have a smaller population of stem cells and a greater population of differentiated cells that are in constant proliferation.…”

Substrate Specificities and Inhibition Pattern of the Solute Carrier Family 10 Members NTCP, ASBT and SOAT

“…In contrast, a transport function for sulfated steroids would not make sense physiologically for ASBT, because relevant levels of sulfated steroid hormones are not present in the lumen of the ileum. SOAT is more widespread in its expression and was detected in germ cells of the testis, skin, placenta, mammary gland and some other hormone-dependent tissues (Geyer et al, 2007;Fietz et al, 2013;Grosser et al, 2013;Karakus et al, 2018). By SOAT-mediated uptake of sulfated steroid hormones from the blood and subsequent cleavage by the steroid sulfatase (so-called intracrine steroid synthesis) seems to contribute to the steroid regulation of many hormone-dependent tissues (Geyer et al, 2017).…”

“…SOAT is expressed in breast cancer and here mediates the uptake of pro-proliferative sulfated estrogen precursors. Inhibition of SOAT had anti-proliferative effects in breast cancer cells in vitro, and so was proposed as potential novel anti-cancer drug target (Karakus et al, 2018).…”

SOAT1 methylation is associated with coronary heart disease

“…SOAT1 is ubiquitously expressed in tissues and cells, while SOAT2 is predominantly expressed in the liver and intestines [23]. Reports indicated that SOAT1 is constitutively expressed and likely functions to maintain the intracellular balance of free and esterified cholesterol, whereas SOAT2 is associated with intestinal cholesterol absorption and hepatocyte-specific functions such as lipoprotein particle assembly and the production of bile, and SOAT1 is responsible for the formation of foam cell in macrophages [24, 25]. Previous studies also reported that SOAT1 was involved in the formation of atherosclerotic plaques, and was involved in regulating inflammation.…”