Estrogen Sulfotransferase (SULT1E1) and NFκβ Confer Matrix Metalloprotease (MMP 2/9) Action in Breast Carcinogenesis

Estrogen (E2) is a signaling molecule that controls cell differentiation/early embryogenesis/organogenesis. Nevertheless, during adolescence/adulthood it influences female reproductive functions via nongenomic (cellular signaling)/genomic (transcriptional signaling) pathways by recruiting a number of genes/proteins.

In postmenopausal women, increased E2 causes malignancies in the breast and gynecologic tissues. An aberrant redox control of the estrogen-metabolizing enzyme like estrogen sulfotransferase (SULT1E1), transcription factors NFκβ/Nrf2, and matrix metalloproteases (MMP 2/9) results in impaired estrogenic signaling.

Here, the tumor and its surrounding tissues underwent a redox-state screening. In rat liver tissues treated with lansoprazole (Nrf2 inducer) and dexamethasone (SULT1E1 inducer), RT-PCR was performed to measure SULT1E1 expression in human breast cancer tissues and the MMP 2/9 activities by gel zymogram technique. Using immunohistochemistry, the location of SULT1E1/NFκβ was examined.

Extensive protein–protein interactions (MMP2/9 and Nrf2) were studied by the STRING Bioinformatics software to characterize metabolic functional dependence. It can be hypothesized transcription factors (NFκβ/Nrf2) influence MMP expressions, which has a major impact on the metastatic transformation of breast cancer. Breast cancers exhibit elevated Nrf2/NFκB/SULT1E1 expression and immunolocalization. Lansoprazole and dexamethasone both demonstrated antioxidant induction by increasing catalase and SOD activities and Nrf2 protein expressions. Statistical implications strongly justify correlations among SULT1E1 and Nrf2 inductions also with antioxidant enzymes. Canonical correlation, multiple comparisons Dunnett’s, and ANOVA test support these statistics. The relation between Nrf2/NFκB is determined by the oxidative stress and MMP-dependent cellular/transcriptional regulations of other biomolecules. Moreover, SULT1E1-mediated E2 levels and MMP functions are determined by this relationship.

The role of MMPs in the severity of human breast carcinogenesis is thought to be carried out by the regulation of NFκβ, SULTN1E1, and Nrf2. This regulatory system may be therapeutically targeted to treat breast cancer.