Genomic Determinants of PIK3CA Mutation-Driven Breast Cancer Initiation
Abstract
Overarching Challenges: One dumb tumor is smarter than 100 cancer biologists is a common phrase that I use when starting cancer biology signaling course for graduate students to highlight complexities in genomic and signaling events in cancer and the need for continued basic research to make cancer a treatable disease. Mutation in a gene called PIK3CA, which is the second most commonly mutated gene in breast cancer, is a typical example of a genomic aberration in cancer that is still full of mysteries with respect to its function. When cancer-enriched mutation in this gene was originally discovered and later identified in 40% of breast cancers, there was significant excitement that targeting this mutated gene would provide a cure for 40% of breast cancers. Although multiple drugs targeting mutant PIK3CA protein have been developed and one of them, alpelisib, is used clinically, response to treatment is not durable. These clinical findings are bringing us back to the drawing board to focus on understanding why tumors with PIK3CA mutations are still not treatable. A new twist to the PIK3CA mutation story has emerged recently. Mutation of this gene is found in normal breast tissues, esophagus, endometrium, and colon without apparent disease. These observations suggest that PIK3CA mutation alone is insufficient to initiate breast cancer and additional genomic aberrations are necessary for the mutant PIK3CA to initiate breast cancer. This dependency of mutant PIK3CA to other genomic aberrations helps the tumor to become smarter as the mutant PIK3CA can piggyback on different types of genomic aberrations to generate multiple tumor types with mutant PIK3CA being the only common mutation across these tumor subtypes. Based on our extensive preliminary data, we propose that genomic aberrations that create BRCAness phenotype (a condition similar to having inherited mutations in breast cancer susceptibility genes BRCA1 and BRCA2) enables the mutant PIK3CA to initiate breast cancer. By understanding mutant PIK3CA-driven breast cancer initiation, this proposal will address the overarching challenge of identifying determinants of breast cancer initiation. Additionally, our studies may revolutionize treatment regimens by replacing them with ones that are more effective and impact survival. Hypothesis and Objectives: Genomic aberrations (aberrant DNA sequence in a region of the breast cell genome in which DNA sequence instead of being present as normal two copies per cell is increased to > two copies) artificially creates BRCAness phenotype. If the cells with these genomic aberrations also harbor PIK3CA mutation, then breast cancer initiates. Luckily, drugs that may be effective against these genomic aberrations have already been developed by us and others. We will determine whether these drugs with and without PIK3CA inhibitor alpelisib are effective against subclass of breast cancers with PIK3CA mutation. Aims and Approaches: We have found that genomic aberrations in two genes called IKBKB and IKBKE could create BRCAness phenotype by activating a common signaling pathway called NF-kappaB (NFkB). Thus, the ability of mutant PIK3CA to cooperate with IKBKB and IKBKE to initiate breast cancer will be investigated in Aim 1. This aim will also characterize three common types to PIK3CA mutations for their ability to cooperate with IKBKB and IKBKE. In the second aim, we will examine whether another genomic aberration called MIR205HG cooperates with mutant PIK3CA to initiate breast cancers. MIR205HG is clever in a way that it can reduce BRCA1 protein levels in cells that do not have BRCA mutation. In both of these aims, we will use breast tissues from healthy donors to establish breast cancer initiation model. The laboratory has >20 years of experience in working on NF-kB signaling and has developed an inhibitor called DMAPT that has completed phase 1 study for leukemia. Breast cancers with BRCAness phenotype can be treated wi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210719
Entities
People
- Harikrishna Nakshatri
Organizations
- Indiana University
- United States Army