Triad entanglement of estrogen-sulfotransferase (SULT1E1), NFκβ and Nrf-2 confers matrix-metalloprotease (MMP 2/9) action in breast carcinogenesis

ABSTRACTEstrogen (E2) is one of the most important signaling molecules that control cell-differentiation/early-embryogenesis/organogenesis in gender-independent manner. Nevertheless, during adolescence/adulthood it influences female reproductive-functions by delicate cellular proliferative-events via nongenomic (cellular-signaling)/genomic (transcriptional-signaling) pathways to recruit a number of genes/proteins. In case of post-menopausal-women high E2 may initiates tumors in breast/gynaecological-tissues. Impired estrogenic signaling may be the results from abnormal redox-regulations of estrogen-metabolizing-enzyme estrogen-sulfotransferase(SULT1E1), transcriptional-factors NFκβ, Nrf-2 and Matrixmetalloproteases (specially MMP 2/9) in the breast-tumor. Here, tumor and its surrounding tissues were obtained from the district-hospital. Intracellular redox-environment of tumors was screened with some in vitro-studies. RT-PCR for SULT1E1 expression and MMP 2/9-zymogram were conducted in lasoprazole (Nrf-2 inducer) or dexamethasone (SULT1E1 inducer) treted rat liver tissues. Immunohistochemistry was performed to analyze SULT1E1/NFκβ localization and MMP 2/9-zymogram in human breast-cancer versus its surrounding tissues. It can be hypothesized that transcription-factors (NFκβ/Nrf-2) imposes effect on MMPs expressions resulting in significant impacts on metastatic transition of breast-cancer. Breast tumor reveals higher (vs surrounding-tissue) expression/immunolocalization of NFκB/SULT1E1 paralleling to our previous finding of Nrf-2 induction. The relation between Nrf2/NFκB is determined by oxidative-stress and by CBP recruitment of HDAC3. Further, this relation is a determinant of MMP-regulations and SULT1E1-mediated E2 levels. Adaptively, augmented Nrf-2 may induce SULT1E1 resulting in lower active-estrogen. The triad regulations of NFκβ, SULT1E1 and Nrf2 are proposed here to execute MMPs function in the severity of human breast-carcinogenesis. Therapeutically this triad system may be effectively targeted for breast cancer treatment. Further studies are necessary in this regard.