ABSTRACT
p110α is a catalytic subunit of phosphoinositide 3-kinase (PI3K), a major downstream effector of receptor tyrosine kinase ErbB2, that is amplified and overexpressed in 20-30% of breast cancers, 40% of which have an activating mutation in p110α. Despite the high frequency of PIK3CA gain-of-function mutations, their prognostic value is controversial. Here, we employ a knock-in transgenic strategy to restrict the expression of an activated form of ErbB2 and p110α kinase domain mutation (p110αHR) in the mammary epithelium. Physiological levels of transgene expression under the control of their endogenous promoters did not result in a major synergistic effect. However, tumors arising in ErbB2/p110αHR bi-genic strain metastasized to the lung with significantly reduced capacity compared to tumors expressing ErbB2 alone. The reduced metastasis was further associated with retention of the myoepithelial layer reminiscent of ductal carcinoma in situ (DCIS), a non-invasive stage of human breast cancer. Molecular and biochemical analyses revealed that these poorly metastatic tumors exhibited a significant decrease in phospho-myosin light chain 2 (MLC2) associated with cellular contractility and migration. Examination of human samples for MLC2 activity revealed a progressive increase in cellular contractility between non-invasive DCIS and invasive ductal carcinoma. Collectively, these data argue that p110αHR mutation attenuates metastatic behavior in the context of ErbB2-driven breast cancer.
Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Class I Phosphatidylinositol 3-Kinases/genetics , Female , Humans , Mutation , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Receptor, ErbB-2/geneticsABSTRACT
Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals dramatic developmental defects in the reproductive organs, mammary glands, and bones of the mice. These observations provide critical insights into the tissue-specific roles of ERα during development and highlights the potential use of our model in further developmental and cancer studies.
Subject(s)
Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Growth and Development/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/physiopathology , Disease Models, Animal , Female , Humans , Male , Mice , Mutation , Sex CharacteristicsABSTRACT
Modeling breast cancer through the generation of genetically engineered mouse models (GEMMs) has become the gold standard in the study of human breast cancer. Notably, the in vivo modeling of the epidermal growth factor receptor (EGFR) family has been key to the development of therapeutics and has helped better understand the signaling pathways involved in cancer initiation, progression and metastasis. The HER2/ErbB2 receptor is a member of the EGFR family and 20% of breast cancers are found to belong in the HER2-positive histological subtype. Historical and more recent advances in the field have shaped our understanding of HER2-positive breast cancer signaling and therapeutic approaches.
