Journal
MOLECULAR CANCER RESEARCH
Volume 16, Issue 6, Pages 1046-1058Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-17-0593
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Funding
- Canadian Institute of Health Research (CIHR)
- Canadian Breast Cancer Foundation
- Breast Cancer Action Kingston
- Kingston General Hospital Foundation
- Canadian Breast Cancer Foundation, Ontario [369649]
- Ontario Trillium Scholarship (OTS, Canada)
- CIHR/Terry Fox Foundation Training Program in Transdisciplinary Cancer Research
- Chinese Government Award for Outstanding Self-financed Students Abroad
- Huang Leadership Development Scholarship
- Vanier Canada Graduate Scholarship
- Queen's University Terry Fox Research Institute Transdisciplinary Training Program in Cancer Research Fellowship
- Dr. Robert John Wilson Graduate Fellowship
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Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death in vitro. PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice in vivo. Interestingly, we also determined that PIK3CAH1047R enhances YAP and TAZ activity in mammary tumorigenesis in vitro. Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LAT-Sindependent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation. (C) 2018 AACR.
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