Breast cancer mutations HER2V777L and PIK3CAH1047R activate the p21-CDK4/6 –Cyclin D1 axis driving tumorigenesis and drug resistance.

In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene pair, with approximately 40% of HER2 mutated breast cancers also having activating mutations in PIK3CA. To study the effects of co-occurring HER2 and PIK3CA mutations, we bred genetically engineered mice with the HER2V777L; PIK3CAH1047R transgenes (HP mice) and studied the resulting breast cancers both in vivo as well as ex vivo using cancer organoids. Overall design: Comparative gene expression profiling analysis of RNA-seq data for WT mice and PIK3CA single mutated mice, HER2 single mutated mice, and PIK3CA/HER2 double mutated mice.