MYC/miR-18a-5p/HIF1A regulatory network confers drug resistance to breast cancer



 DESCRIPTION (provided by applicant): Metastatic relapse is the leading cause of death for patients with basal-like breast cancer (BLBC), the most aggressive subtype that accounts for ~15% of all breast cancers. BLBC tends to affect younger patients and metastasize to lung and brain. Systematic chemotherapy is the standard treatment for patients with BLBC tumors. Despite initial high response rates to chemotherapy, manifested by tumor regression, most patients (~85%) experience metastatic relapse within 10 years. Currently there is no effective way to treat or prevent metastatic relapse because we do not fully understand what enables tumor cells to escape cytotoxicity of chemotherapy. Our recent studies and analysis of The Cancer Genome Atlas (TCGA) data suggest that two distinct phenotypic states, MYC-driven proliferative and drug-sensitive state and HIF1A-driven invasive and drug-resistant state, coexist among BLBC tumor cells. We found that miR-18a-5p plays a key role in regulating phenotypic state of BLBC cells by suppressing HIF1A activation, and derepression of HIF1A due to miR-18a-5p downregulation is sufficient to convert tumor cells into a drug resistant state. We propose to examine whether increasing cellular content of miR-18a-5p to suppress HIF1A activation or inhibiting metabolic enzymes regulated by HIF1A can be used for therapeutic purpose to increase chemosensitivity of BLBC cells. The results from these studies will contribute to a broader understanding of the function of miRNAs in regulating cell phenotype, and advance our understanding of HIF1A-mediated drug resistance.