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Mutant PI3K cooperates with HER2 to promote mammary tumor formation and induces trastuzumab resistance in vivo

ABSTRACT: HER2 (ERBB2) gene amplification and PIK3CA mutations often co-occur in breast cancer, and aberrant activation of the PI3K pathway has been implicated in resistance to HER2-directed therapies. We have created a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in their mammary glands developed tumors with a significantly shorter latency compared to mice expressing either oncogene alone. By microarray analysis, HER2-driven tumors clustered with the luminal subtype, whereas HER2+PIK3CA and PIK3CA-driven tumors were associated with the claudin-low breast cancer subtype. In accordance, PIK3CA and HER2+PIK3CA tumors expressed elevated levels of EMT and stem cell markers, and cells from HER2+PIK3CA tumors more efficiently formed mammospheres, providing further evidence that activated PIK3CA may enrich for cancer stem cells. Finally, HER2+PIK3CA tumors are resistant to the HER2 antibody trastuzumab; resistance is partially reversed by the addition of a PI3K inhibitor. Taken together, these studies suggest that the co-expression of HER2 and PI3KH1047R in the mouse mammary gland accelerates the formation of aggressive, trastuzumab-resistant tumors. referenceXsample

ORGANISM(S): Mus musculus  

SUBMITTER: Charles Perou   Carlos L Arteaga  Adam Pfefferle  Charles M Perou  Ariella B Hanker 

PROVIDER: E-GEOD-41118 | ArrayExpress | 2013-09-03



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Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.

Hanker Ariella B AB   Pfefferle Adam D AD   Balko Justin M JM   Kuba María Gabriela MG   Young Christian D CD   Sánchez Violeta V   Sutton Cammie R CR   Cheng Hailing H   Perou Charles M CM   Zhao Jean J JJ   Cook Rebecca S RS   Arteaga Carlos L CL  

Proceedings of the National Academy of Sciences of the United States of America 20130812 35

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  ...[more]

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