Title: ONCOSTATIN M PROMOTES CHROMOSOMAL INSTABILITY IN ER+ BREAST CANCER CELLS

Program: Biology MS

Committee Chair: Cheryl Jorcyk

Committee: Cheryl Jorcyk, Allan Albig, Ken Cornell

Abstract: Breast cancer is the second leading cause of cancer mortality among women in the United States, largely attributed to metastatic spread to distant tissues. While the five-year survival rate for breast cancer patients with regional metastasis is 87%, it declines to 32% in patients with distant metastasis. It is known that mutational burden is increased in metastatic breast cancer tissue, and that mutations drive breast cancer metastasis. Breast cancer progression is driven by mutations because they promote intratumoral heterogeneity, and this genetic variation gives rise to cells with enhanced metastatic characteristics and treatment resistance. However, the role of Oncostatin M (OSM) in genetic stability has not yet been reported. Notably, OSM is an inflammatory cytokine that has been shown to promote breast cancer metastasis and is associated with reduced overall survival in breast cancer patients. We wanted to explore the hypothesis that chromosomal instability is induced by OSM and is a contributing factor to OSM-driven breast cancer metastasis. We demonstrate that OSM increased micronuclear frequency in the luminal A breast cancer cell lines tested. Additionally, OSM significantly increases DNA fragmentation in T47D cells. OSM differentially regulates PPIF and CAT, which regulate mitochondrial function and redox homeostasis. Importantly, micronuclear frequency was rescued in OSM-treated T47D cells by the reactive oxygen species scavenger, N-acetylcysteine. Collectively, these results support a redox-dependent mechanism for OSM-induced genetic instability. These findings suggest that luminal A breast cancer patients may respond best to an OSM-targeting therapy, and that this therapy would prevent the progression of breast cancer by reducing genetic instability.