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Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies
Open accessAbstract
Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.
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“Supporting this possibility, a recent study showed that transgenic mammary tumors expressing HER2 and PIK3CAH1047R were completely resistant to the combinations of trastuzumab plus pertuzumab and trastuzumab plus lapatinib.”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Hanker et al., 2013
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Metadata
- Authors
- Hanker, A. B., Pfefferle, A. D., Balko, J. M., Kuba, M. G., Young, C. D., Sánchez, V., Sutton, C. R., Cheng, H., Perou, C. M., Zhao, J. J., Cook, R. S., & Arteaga, C. L.
- Affiliations
- Departments of aMedicine,
- Departments of bPathology and Laboratory Medicine and
- Vanderbilt University (US)
- Pathology, and
- Departments of eCancer Biology and
- University of North Carolina at Chapel Hill (US)
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-08-12
- Volume
- 110
- Issue
- 35
- Pages
- 14372-14377
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3761610
- OpenAlex
- W2056427943
- Cited by
- 203
- References
- 41
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 21 · 2022: 16 · 2021: 16 · 2020: 13 · 2019: 17 · 2018: 11 · 2017: 11 · 2016: 23 · 2015: 22 · 2014: 23
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense
- Breast Cancer Research Foundation
- Entertainment Industry Foundation (SU2C-AACR-DT0209)
- Vanderbilt University
- Vanderbilt-Ingram Cancer Center (P30 CA 68485)
- National Institutes of Health (5r01ca138255-03)
- Stand Up To Cancer (SU2C‐AACR‐DT0209)
- National Cancer Institute (P50 CA98131, R01CA-138255, R01 CA80195, P30 CA 68485, CA148761, R01CA143126, R01CA080195, R01CA134502, R01CA172461, CA138255, P50CA098131, P50 CA 58223, P30CA068485, P50CA058223, R01CA148761)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- PIK3CA mutation, HER2 overexpression, breast cancer, PI3K signaling, trastuzumab resistance, lapatinib, pertuzumab, combination therapy resistance, mammosphere formation, epithelial-mesenchymal transition, claudin-low breast cancer, luminal breast cancer, lung metastasis, mammary tumors, PI3K inhibitors, mouse tumor model
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Lung Neoplasms, Mammary Neoplasms, Experimental, Mice, Transgenic, Mutation, Genes, erbB-2, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Mice, Class I Phosphatidylinositol 3-Kinases, Epithelial-Mesenchymal Transition
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