Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer
- Author(s)
- Simond, AM; Bui, T; Zuo, D; Sanguin-Gendreau, V; Rao, T; Phillips, WA; Cardiff, RD; Muller, WJ;
- Details
- Publication Year 2022-06,Volume 41,Issue #25,Page 3445-3451
- Journal Title
- Oncogene
- Publication Type
- Research article
- Abstract
- p110alpha 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 p110alpha. 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 p110alpha kinase domain mutation (p110alpha(HR)) 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/p110alpha(HR) 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 p110alpha(HR) mutation attenuates metastatic behavior in the context of ErbB2-driven breast cancer.
- Keywords
- *Breast Neoplasms/genetics/pathology; *Carcinoma, Intraductal, Noninfiltrating; Class I Phosphatidylinositol 3-Kinases/genetics; Female; Humans; Mutation; Phosphatidylinositol 3-Kinase/genetics; Phosphatidylinositol 3-Kinases/genetics/metabolism; Receptor, ErbB-2/genetics
- Department(s)
- Laboratory Research
- PubMed ID
- 35538223
- Publisher's Version
- https://doi.org/10.1038/s41388-022-02323-9
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-04-04 05:25:02
Last Modified: 2025-04-04 05:39:07