Physiological Levels of <em>Pik3ca</em>^H1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors

<div><p><em>PIK3CA</em>, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant <em>PIK3CA</em> in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, <em>Pik3ca^H1047R</em>, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin⁻; CD29^lo; CD24⁺; CD61⁺) cell population. The <em>Pik3ca^H1047R</em> expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (&gt;12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant <em>Pik3ca</em> is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. <em>In vitro</em> induction of <em>Pik3ca^H1047R</em> in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous <em>PIK3CA</em> gene, will thus be a valuable tool for investigating the role of <em>Pik3ca^H1047R</em> mutation in mammary tumorigenesis both <em>in vivo</em> and <em>in vitro</em>.</p>