Abstract P3-08-04: Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations

Abstract Human breast cancer (BRCA) shows tremendous genomic, gene expression, clinical, and phenotypic heterogeneity. Known driver gene alterations can only explain a portion of this heterogeneity, some of which likely arise from variation in the target cell for transformation, in addition to incompletely understood gene copy number and epigenetic alterations. These factors are difficult to identify with certainty using human patient samples due to widely varying germline genetic backgrounds, thousands of gene copy and epigenetic changes per sample, and, unknown target cell transformation. Activating mutations in the p110α catalytic subunit of PI3K are one of the most common genetic alterations in human BRCA. Here, we report results from two Sleeping Beauty (SB) transposon-accelerated mouse models of Pik3ca-mutant mammary cancer showing how genotype-phenotype correlations can be drawn providing strong candidates for mediating tumor phenotypes, including estrogen-receptor (ER)-dependent gene expression, high cell cycle activity, and immune cell exclusion. We used SB transposon mutagenesis in mice on a Pik3caH1047R activated mutant background to model mammary cancer development in two different mammary epithelial compartments. Both the target cell for mutagenesis and the specific transposon-induced mutations correlated with specific tumor phenotypes, including whether the tumors were ER positive or negative. RNA sequencing of tumors revealed novel genotype-phenotype correlations implicating specific transposon-altered gene drivers of high cell cycle activity, ER-dependent gene expression, and white blood cell exclusion from the tumor. Many transposon-implicated genes are altered at the gene copy number or epigenetic/methylation level in human BRCA, and several were functionally validated. These models provide a source of genetically heterogenous mouse mammary tumors with a uniform initiating mutation, Pik3caH1047R, useful for identifying cooperating pathways and drivers of specific tumor phenotypes. Citation Format: Morito Kurata, Emiily Pope, Jingmin Shu, Wenlin Yuan, Wendy Hudson, Mark Sokolowski, Setareh Bagherzadeh, Zora Modrusan, Eric Stawiski, Steffen Durinck, Sekar Seshigiri, Aaron Sarver, Nuri Temiz, David Largaespada. Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-04.