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.
Highlights
Estrogens play a pivotal role in the development and proliferation of hormone-dependent breast cancer, which represents the most common type of cancer in women (Conner et al, 2008)
In order to analyze sodium-dependent organic anion transporter (SOAT) expression in different types of breast cancer, the OriGene TissueScanTM Breast Cancer cDNA Arrays I-IV were screened for SOAT expression by real-time PCR
SOAT mRNA expression was normalized by SYMPK expression, which has previously demonstrated low variability of expression in breast cancer tissue and cell lines (Tilli et al, 2016)
Summary
Estrogens play a pivotal role in the development and proliferation of hormone-dependent breast cancer, which represents the most common type of cancer in women (Conner et al, 2008). In contrast to free estrogens (E1 and E2), the sulfoconjugated steroid forms, in particular estrone-3-sulfate (E1S) and DHEAS, persist at higher plasma concentrations even after menopause (Rémy-Martin et al, 1983; Geisler, 2003). These sulfo-conjugated steroids can be re-converted into active free estrogens in breast cancer tissue via cleavage of the sulfate group by the STS and further conversion by the enzymes 3βhydroxysteroid dehydrogenase and aromatase in the case of DHEA (Santner et al, 1986; Pasqualini et al, 1997; Labrie et al, 1998; Suzuki et al, 2005; Sasano et al, 2006). Inhibitors of STS (STX64) and aromatase (anastrozole, letrozole) can block this intracrine formation of estrogens and, are used for clinical (aromatase inhibitors) or experimental (STS inhibitors) breast cancer therapy (Santen and Harvey, 1999; Stanway et al, 2007)
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