Carolyn Klinge, Professor of Biochemistry and Molecular Genetics at the University of Louisville School of Medicine, Kentucky, USA, will give a lecture titled HNRNPA2B1 reduces miRNAs Targeting Key Enzymes in the Serine Synthesis Pathway to Promote Endocrine-Resistance in Breast Cancer Cells, in room 343 in Læknagarður.
After her lecture, GPMLS will invite students/post-docs that sign up here to lunch with Professor Klinge at Duck&Rose restaurant.
Abstract: Despite the successful combination of therapies improving survival of estrogen receptor α (ER+) breast cancer patients with resistant metastatic disease, mechanisms for acquired endocrine resistance remain to be fully elucidated. The RNA binding protein HNRNPA2B1 (A2B1), a reader of N(6)-methyladenosine (m6A) in transcribed RNA, is upregulated in endocrine-resistant, ER+ LCC9 and LY2 cells compared to parental MCF-7 endocrine-sensitive luminal A breast cancer cells. Pathway analysis of the miRNA-seq transcriptome of MCF-7 cells transiently overexpressing A2B1 identified the serine family amino acid metabolic process pathway. Increased expression of two key enzymes in the serine synthesis pathway (SSP), phosphoserine aminotransferase 1 (PSAT1) and phosphoglycerate dehydrogenase (PHGDH), correlate with poor outcomes in ER+ breast patients who received tamoxifen (TAM). PSAT1 and PHGDR were higher in LCC9 and LY2 cells compared to MCF-7 cells and their knockdown enhanced TAM-sensitivity in the TAM-resistant cell. Here we demonstrate that stable, modest overexpression of A2B1 in MCF-7 cells (MCF-7-A2B1) resulted in increased PSAT1 and PHGDH and endocrine-resistance. We identified four miRNAs downregulated in MCF-7-A2B1 cells that directly target the PSAT1 3´UTR (miR-145-5p and miR-424-5p), and the PHGDH 3´UTR (miR34b-5p and miR-876-5p) in dual luciferase assay. Lower expression of the miR-145-5p and miR-424-5p in LCC9 cells correlated with increased PSAT1 and lower expression of miR-34b-5p and miR-876-5p in LCC9 cells correlated with increased PSAT1 and lower expression regulated miRNAs restored endocrine-therapy sensitivity in endocrine-resistant LCC9 cells. Overall, our data suggest a role for decreased A2B1-regulated miRNAs in endocrine-resistance and upregulation of the SSP to promote tumor progression in ER+ breast cancer.
