The H1047R PIK3CA oncogene induces a senescence-like state, pleiotropy and acute HSP90 dependency in HER2+ mammary epithelial cells.

Autor:	Chakrabarty A, Surendran S; Department of Life Sciences, Shiv Nadar University, Uttar Pradesh, India., Bhola NE; IDEAYA Biosciences, South San Francisco, CA, USA., Mishra VS; Department of Life Sciences, Shiv Nadar University, Uttar Pradesh, India., Wani TH; Department of Life Sciences, Shiv Nadar University, Uttar Pradesh, India., Baghel KS; Department of Life Sciences, Shiv Nadar University, Uttar Pradesh, India., Arteaga CL; University of Texas Southwestern and Simmons Comprehensive Cancer Center, Dallas, TX, USA., Garg R; Department of Life Sciences, Shiv Nadar University, Uttar Pradesh, India., Chowdhury G; Department of Chemistry, Shiv Nadar University, Uttar Pradesh, India.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2019 Oct 16; Vol. 40 (10), pp. 1179-1190.
DOI:	10.1093/carcin/bgz118
Abstrakt:	In pre-clinical models, co-existence of Human Epidermal Growth Factor Receptor-2 (HER2)-amplification and PI3K catalytic subunit (PIK3CA) mutations results in aggressive, anti-HER2 therapy-resistant breast tumors. This is not always reflected in clinical setting. We speculated that the complex interaction between the HER2 and PIK3CA oncogenes is responsible for such inconsistency. We performed series of biochemical, molecular and cellular assays on genetically engineered isogenic mammary epithelial cell lines and breast cancer cells expressing both oncogenes. In vitro observations were validated in xenografts models. We showed that H1047R, one of the most common PIK3CA mutations, is responsible for endowing a senescence-like state in mammary epithelial cells overexpressing HER2. Instead of imposing a permanent growth arrest characteristic of oncogene-induced senescence, the proteome secreted by the mutant cells promotes stem cell enrichment, angiogenesis, epithelial-to-mesenchymal transition, altered immune surveillance and acute vulnerability toward HSP90 inhibition. We inferred that the pleiotropism, as observed here, conferred by the mutated oncogene, depending on the host microenvironment, contributes to conflicting pre-clinical and clinical characteristics of HER2+, mutated PIK3CA-bearing tumor cells. We also came up with a plausible model for evolution of breast tumors from mammary epithelial cells harboring these two molecular lesions. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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