Determining the Role of Genetic Variants Linked to PIK3CA and Metabolic Regulators in Breast Cancer

Tanish Gandhi, Dr. Amanda Toland, Department of Cancer Biology and Genetics, The Ohio State University, 281 W. Lane Avenue, Columbus, Ohio, 43210.

The PI3K/AKT/mTOR pathway is central to cancer proliferation and affects apoptosis, migration, and glucose metabolism in various cancer types. Breast cancer has activation of this pathway through oncogenic mutations in the PIK3CA gene. A phenomenon connected to the PI3K pathway is the Warburg effect, a tendency for cancer cells to use glycolysis for energy, even under aerobic conditions. Within the PI3K pathway, there is a lack of understanding regarding changes in tumor metabolism caused by PIK3CA mutations and potential effects when combined with other glycolytic mediators. In preliminary work, I conducted an in silico search of germline genetic variants associated with PIK3CA mutation status in breast cancer for relevance to genes involved in glucose metabolism. One gene identified was KDM8 (also known as JMJD5), which is 30kb from rs4493040, a single nucleotide variant (SNV) associated with PIK3CA mutation status. Existing data shows rs4493040 linked to enhancer activity in breast cancer cell lines and mammary epithelial cells. KDM8 is a co-activator of HIF-1A, a hypoxia regulator of glycolytic genes. Similarly, PI3K is a significant regulator of HIF-1A through mTOR. Based on these studies, we hypothesize that the rs4493040 variant impacts KDM8 gene expression and subsequent HIF-1A activation. Additionally, we expect that KDM8 levels will act synergistically with PIK3CA mutations to enhance HIF-1A metabolism gene targets in glycolysis. We aim to test the role of the rs4493040 variant through luciferase assays and chromatin immunoprecipitation (ChIP) studies. We hope to demonstrate a synergistic effect between the PI3K pathway and the KDM8 gene in existing MCF10A breast epithelial cells with and without CRISPR-induced PIK3CA mutations to test the association with the HIF-1A complex. From characterizing these mutations and pathway alterations, we hope to better understand tumor biology and metabolism to identify therapeutic targets for breast cancer treatment.

Additional Abstract Information

Presenter: Tanish Gandhi

Institution: The Ohio State University

Type: Poster

Subject: Biology

Status: Approved

Time and Location

Session: Poster 3
Date/Time: Mon 4:30pm-5:30pm
Session Number: 3090