PTEN loss rescues apoptosis in E-cadherin deficient mammary epithelial cells, resulting in development of classical invasive lobular carcinoma in mice

Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. E-cadherin loss represents a hallmark of ILC, but is insufficient to induce ILC in mice. While driver mutations are mostly unknown, activating PI3K mutations or PTEN inactivation are frequently observed in human ILC. Here we describe a novel mouse model of classical ILC (CLC), the main histological subtype based on somatic inactivation of E-cadherin and PTEN in mammary epithelium. PTEN inactivation rescues apoptosis induced by E-cadherin loss and triggers rapid formation of invasive mammary tumors that recapitulate histological and molecular features, ER-status, growth kinetics, metastatic behavior and tumor microenvironment of human CLC. Importantly, inactivation of E-cadherin and PTEN is sufficient and thus causal to induce CLC. This mouse model provides novel insights into the development and disease progression of CLC and shows that inhibition of PI3K signaling may be a novel strategy to target CLC.