Contrasting roles of MutSα and MutLα in basal-like breast cancer 3317

Description Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer, marked by high genomic instability. Due to increased genetic heterogeneity, BLBC cells upregulate DNA repair pathways. Therefore, DNA repair-based therapies have significant potential for BLBC patients. While FDA-approved Poly (ADP-ribose) polymerase inhibitors target BLBC patients with BRCA1/2 mutations, most BLBC patients lack BRCA1/2 mutations and effective therapeutic targets. Using TCGA dataset, we identified that mismatch repair (MMR) proteins MSH2 and MSH6 (referred to as MutSα) are elevated in BLBC and correlate with poor patient survival. Conversely, MMR proteins MLH1 and PMS2 (referred to as MutLα) are downregulated at the mRNA level and show no survival correlation. In contrast to their classical tumor suppressor roles, our data suggest that MutSα promotes BLBC metastasis, while MutLα suppresses metastasis. Mechanistically, our preliminary data indicate that MutSα influences chemokine expression and immune cell infiltration in the tumor microenvironment (TME), potentially by suppressing interferon alpha/beta receptor 1 (IFNAR1) via direct binding to its promoter. We hypothesize that MutSα is significantly induced in BLBC, and acts in a non-canonical way to promote metastasis via IFNAR1 suppression and immunomodulation. Our future study will delineate the novel immunoregulatory mechanism of MutSα, in contrast to MutLα, providing a strong rationale for targeting MutSα in BLBC therapy. Funding Sources R01CA260239 NIH/NCI Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)