Gaorav P. Gupta

My research interest is to understand the interplay between genome integrity pathways and breast cancer initiation, progression, and response to therapy. The DNA damage response (DDR) is an evolutionarily conserved network of DNA damage sensors, mediators, and effectors that is responsible for maintaining genomic integrity in the face of intrinsic (e.g. oxidized DNA, incorporated ribonucleotides, replication-associated single- and double-strand breaks) and extrinsic (e.g. ionizing radiation, alkylating agents, other clastogen exposures) DNA damage. Germline aberrations in the DDR pathway are known to predispose to cancer (e.g. BRCA1-2, XPA-G, FANCA-P, etc.), but the significance of the DDR in sporadic tumorigenesis is only beginning to emerge.

Recent insights from cancer genome sequencing projects have revealed the remarkable complexity and heterogeneity of genomic aberrations that are observed in human breast cancer. The molecular bases for this genomic complexity remain largely unknown; however, patterns of mutational and structural aberrations have emerged from analyses of cancer genome datasets that suggest underlying defects in DNA repair processes that normally preserve genome integrity during cellular replication. Thus, functional impairment of DDR pathways in sporadic cancers may be a major driver of genetic heterogeneity that fuels progression to metastatic and therapy-resistant disease. Our long-term research goals are to understand the mechanisms that give rise to genomic instability in breast cancer and to identify the molecular vulnerabilities associated with this cancer-specific phenotype. With an improved understanding of these mechanisms and vulnerabilities, we hope to uncover new therapeutic approaches for the most genomically and phenotypically heterogeneous human breast cancers, which are often also the most refractory to treatment.

Our lab utilizes a variety of complementary approaches to tackle this complex topic. Innovative breast cancer mouse models, primary mammary epithelial cell culture, DNA repair/checkpoint assays, RNAi- and CRISPR-based functional genetics, and a variety of genomic assays are all currently being employed.