Contrasting roles of MSH2 and MLH1 in basal-like breast cancer

Basal-like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer, characterized by high genomic instability. Because of higher mutational load and genetic heterogeneity in BLBC, cancer cells tend to upregulate DNA repair pathways. Therefore, DNA repair-based therapies are considered to have significant potential for BLBC patients. PARP (Poly (ADP-ribose) polymerase) inhibitors are approved by FDA to treat a subset of BLBC patients with BRCA1/2 mutations. However, most BLBC patients have wildtype BRCA1/2 and lack good therapeutic targets. We analyzed all available DNA repair genes and proteins using TCGA RNA-sequencing and RPPA (Reverse Protein Phase Array) data. Our investigation identified that mismatch repair (MMR) proteins MSH2 and MSH6 (referred to as MutSalpha) are highly elevated in BLBC and their higher expressions are correlated to poor survivals of BLBC patients. Conversely, MLH1 and PMS2 (referred to as MutLalpha), the second major component of the MMR machinery, are downregulated at the mRNA level and cannot predict patient survival in BLBC. In contrast to the known tumor suppressor functions of MMR proteins, our data indicates that MSH2 promotes BLBC metastasis; MLH1, on the other hand, is associated with decreased tumor progression and metastasis. The contrasting functions of MSH2 and MLH1 have never been reported. At the mechanistic level, our data strongly indicate that MSH2, in contrast to MLH1, regulates the expression of chemokines and tumor infiltrating immune cells. Further investigation at the genomic level suggests that MSH2 regulates the expression of interferon alpha/beta receptor 1 ( IFNAR1) , which plays various roles in the tumor microenvironment (TME) for potential antitumor effects. Deletion of MSH2 initiates a chain of immune reactions via the upregulation of IFNAR1 expression which explains a highly immune active TME in tumors with MSH2-deficiency. Our study supports the contrasting functions of MSH2 and MLH1 in BLBC progression are due to their distinct transcriptional regulation of immune related genes, not related to their canonical mismatch repair activity. These findings challenge the universal paradigm that all MMR proteins have similar effects on tumor progression or suppression.