Oestrogen receptor-independent actions of oestrogen in cancer.

Oestrogen, the primary female sex hormone, plays a significant role in tumourigenesis. The major pathway for oestrogen is via binding to its receptor [oestrogen receptor (ERα or ß)], followed by nuclear translocation and transcriptional regulation of target genes. Almost 70% of breast tumours are ER + , and endocrine therapies with selective ER modulators (tamoxifen) have been successfully applied. As many as 25% of tamoxifen-treated patients experience disease relapse within 5 years upon completion of chemotherapy. In such cases, the ER-independent oestrogen actions provide a plausible explanation for the resistance, as well as expands the existing horizon of available drug targets. ER-independent oestrogen signalling occurs via one of the following pathways: signalling through membrane receptors, oxidative catabolism giving rise to genotoxic metabolites, effects on mitochondria and redox balance, and induction of inflammatory cytokines. The current review focuses on the non-classical oestrogen signalling, its role in cancer, and its clinical significance.

Mitochondrial ribosomal small subunit (MRPS) MRPS23 protein-protein interaction reveals phosphorylation by CDK11-p58 affecting cell proliferation and knockdown of MRPS23 sensitizes breast cancer cells to CDK1 inhibitors.

BACKGROUND: Post-translational modification of some mitoribosomal proteins has been found to regulate their functions. MRPS23 has been reported to be overexpressed in various cancers and has been predicted to be involved in increased cell proliferation. Furthermore, MRPS23 is a driver of luminal subtype breast cancer. However, its exact role and function in cancer remains unknown. METHODS AND RESULTS: Our previous study identified protein-protein interactions involving MRPS23 and CDK11A. In this study, we confirmed the interaction of MRPS23 with the p110 and p58 isoforms of CDK11A. Phosphoprotein enrichment studies and in vitro kinase assay using CDK11A/cyclin D3 followed by MALDI-ToF/ToF analysis confirmed the phosphorylation of MRPS23 at N-terminal serine 11 residue. Breast cancer cells expressing the MRPS23 (S11G) mutant showed increased cell proliferation, increased expression of PI3-AKT pathway proteins [p-AKT (Ser47), p-AKT (Thr308), p-PDK (Ser241) and p-GSK-3ß (Ser9)] and increased antiapoptotic pathway protein expression [Bcl-2, Bcl-xL, p-Bcl2 (Ser70) and MCL-1] when compared with the MRPS23 (S11A) mutant-overexpressing cells. This finding indicated the role of MRPS23 phosphorylation in the proliferation and survival of breast cancer cells. The correlation of inconsistent MRPS23 phosphoserine 11 protein expression with CDK11A in the breast cancer cells suggested phosphorylation by other kinases. In vitro kinase assay showed that CDK1 kinase also phosphorylated MRPS23 and that inhibition using CDK1 inhibitors lowered phospho-MRPS23 (Ser11) levels. Additionally, modulating the expression of MRPS23 altered the sensitivity of the cells to CDK1 inhibitors. CONCLUSION: In conclusion, phosphorylation of MRPS23 by mitotic kinases might potentially be involved in the proliferation of breast cancer cells. Furthermore, MRPS23 can be targeted for sensitizing the breast cancer cells to CDK1 inhibitors.

Mitochondrial ribosomal small subunit proteins (MRPS) MRPS6 and MRPS23 show dysregulation in breast cancer affecting tumorigenic cellular processes.

Human Mitoribosomal Small Subunit unit (MRPS) family of genes appears to have role in cancer. Gene expression analysis of select MRPS genes (n = 9) in 15 cancer cell lines showed altered expression in cancer cells. Protein levels of MRPS6, MRPS23 showed significant overexpression in breast cancer cells and tissues. Interestingly, their overexpression did not correlate with mitochondrial ribosome translated COX2 protein levels in breast cancer. Subcellular fractionation analysis showed a distinct presence of MRPS23 in the nuclear fraction. GST/MRP6 and GST/MRPS23 pulldown assays identified 32 novel protein-protein interactions (PPIs) and MRPS23-RIPK3 interaction was validated. Co-expression module identification tool (CEMi) analysis of breast cancer gene expression and MRPS6 and MRPS23 interactions revealed hub interactions in gene expression modules having functional roles in cancer-associated cellular processes. Based on PPI network analysis a novel interaction MRPS23-p53 was validated. Knockdown of MRPS6 and MRPS23 decreased proliferation, expression of select mesenchymal markers, oncogenes, and increased expression of tumor suppressor genes. Taken together present study has revealed that MRPS6 and MRPS23 genes have pro-tumorigenic functions in breast cancer.