Looking for the molecular bridge between sex hormone-binding globulin (SHBG) and breast cancer cells
F. Marano2, M. Catalano1,2, R. Frairia2, G. Boccuzzi1,2 & N. Fortunati1
Sex Hormone-Binding Globulin (SHBG), the specific plasma carrier for sex steroids, interacts with cell membranes. In breast cancer cells, SHBG-cell interaction is closely related to estrogen-sensitivity and it is followed by a well-defined cascade of events. Soon after SHBG binding to cell membranes, cAMP accumulates in the breast cancer cells, activates PKA that in turn suppresses estradiol-induced ERK activation. ERK inhibition abolishes the anti-apoptotic effects of estradiol and reduces ERα transcriptional activity. The final result is a significant inhibition of estradiol-induced proliferation. The cell membrane molecule SHBG interacts with has never been certainly identified. A number of candidates, generally being part of the matrix-associated proteins, have been suggested, such as megalin and fibulin. The aim of the present study was to investigate the expression and potential function in SHBG-cell interaction of megalin and fibulin1 and 2, in estrogen-sensitive breast cancer cells (MCF-7 and T47D) where SHBG interaction and anti-estrogenic effect had been widely described. Megalin, fibulin 1 and 2 gene expression was evaluated in both cell lines in basal condition and after estradiol treatment with Real time PCR. Megalin and fibulin 2 were not expressed. Fibulin 1 expression, already detectable in basal condition, was increased by estradiol. The results were confirmed by Western blot, that allowed us to observe also the correct expression of the protein in cell membranes. Finally, immunofluorescence experiments in MCF-7 cells showed a colocalization of fibulin 1 and SHBG on membranes. We, therefore, suggest that fibulin 1 is likely to be the bridge between SHBG and breast cancer cells. SHBG, interacting with fibulin 1 communicates with breast cancer cell, triggers its molecular mediators, and, at the end, blocks estradiol-induced cell growth.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.