The shbg Gene and Hormone Dependence of Breast Cancer: A Novel Mechanism of Hormone Dependence of MCF-7 Human Breast Cancer Cells Based upon SHBG.

Abstract

BACKGROUND: SHBG (sex hormone binding globulin) is a 45 kDa glycoprotein thatbinds sex steroid with high specificity and affinity. SHBG is produced in various tissues including breast, liver, endometrium, and prostate via activated ER alpha and is secreted into plasma. SHBG regulates the activity of bioavailable sex steroid in plasma and in cells and also modulates cell growth regulation. METHODS: The predictive value of SHBG on the efficacy of hormone therapy against human breast cancer was determined. To evaluate the role of shbg gene expression in estrogen-dependent cell growth of MCF-7 breast cancer, cDNA cloning and determination of the expression of the shbg gene of MCF-7 cells was performed using PCR, RT-PCR Southern blotting. RESULTS: The SHBG titer (17 beta -estradiol binding capacity of SHBG) showed high predictability for the hormone dependence of breast cancer. Tumors of patientswith high SHBG titers showed a 91.8% response rate (N = 49). In contrast, tumors of patients with low SHBG titers showed only an 8.2% response rate (N = 61). >From our experimental results using MCF-7 cells, it is suggested that the SHBG titer includes SHBG secreted from liver and breast cancer cells. MCF-7 cells showed high expression of the wild type shbg gene, hybridized with Hammond's SHBG probe, which represents the 3'portion of SHBG-cDNA cloned from hepatocytes. E2 (17 beta-estradiol) induced the expression of the wild type shbg gene. However, the exon VII splicing variant of the shbg gene did not respond to E2 induction. CONCLUSIONS: From our results and the reports of other investigators, it is suggested that loss of hormone dependence in breast cancer may be caused by the loss of wild type shbg gene and the appearance of the exon VII splicing variant.The shbg-E2 complex binds to SHBG receptor (SHBGR) in cell membrane and internalizes through SHBGR mediated endocytosis causing the production of intracellularcAMP and E2-responsive second messenger. SHBG functions as a nuclear protein. From these data, we prepared a model of a novel mechanism of hormone dependence of breast cancer based upon SHBG and the shbg gene.