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.