Katerina Fagan-Solis, Ph.D. is a Senior Postdoc in the laboratory of Gaorav Gupta, MD/Ph.D. at the Lineberger Comprehensive Cancer Center at UNC Chapel Hill. She received her Ph.D. from the MCB Program at UMass Amherst in 2013 (Arcaro Lab).

Unraveling novel drivers of rampant genomic instability in breast cancer

Widespread chromosomal instability is a hallmark feature of Triple-Negative Breast Cancer (TNBC), yet the origins of this phenotype are poorly understood. To maintain genome integrity, cells have an elaborate DNA damage response (DDR) mechanism that functions to repair damaged DNA efficiently and commits cells to death if damage is irreparable. An important component of the DDR is the p53 pathway, which is altered in nearly all TNBC but is not currently therapeutically targetable. What is not known is whether alterations in p53-independent DDR mechanisms also drive tumorigenesis and rampant genomic instability in TNBC. Understanding these pathways is important because they may expose tumor-specific vulnerabilities in DNA repair that may be therapeutically exploited. We have developed a novel murine model of TNBC that leverages CRISPR/Cas9 to engineer specific DDR mutations of interest simultaneously with driver oncogenic mutations. Using this model, we demonstrate that deficiency in the Mre11 DDR pathway drives uncontrolled proliferation and genomic instability of TNBC through a p53-independent mechanism. We also observe Mre11 pathway deficiency in a subset of human TNBC, which correlates with increased sensitivity to specific types of DNA damaging chemotherapy. Thus, evaluating TNBC for deficiency in DDR pathway components beyond p53 represents an attractive opportunity for therapeutic exploitation.