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

Abstract

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 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-tomesenchymal 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.

Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer*

“…Mice were purchase from Harlan laboratories. A MMTV/rtTA ϫ tet-op/ PIK3CA H1047R mammary tumor was initially harvested from a female transgenic mouse (11,12) and homogenized in serum-free media with gentleMACS C Tubes (Miltenyi Biotec, Bergisch Gladbach, Germany). Large tissue fragments were removed by brief, low-speed centrifugation with the liquid and smaller tumor fragments transferred to a fresh conical tube that was centrifuged at 200 ϫ g; the tissue pellet was resuspended in 4 ml matrigel diluted with 50% PBS.…”

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

“…Transgenic mice that overexpress mutant PIK3CA in conjunction with HER2/neu recapitulate resistance to anti-HER2/neu therapies (17), and conditionally overexpressed mutant PIK3CA in the mammary gland gives rise to tumors at long latency that regress upon oncogene withdrawal (18). Although these observations contribute to the rationale for targeting PI3K pathway components in breast cancer, they use a model in which mutant PIK3CA is expressed at unphysiological levels and serves as the initiating event.…”

PIK3CA rs7640662 (C/G) single nucleotide polymorphism lacks association with breast cancer cases in Persians

“…Her2 amplifi cation and PIK3CA mutations often coexist in breast cancer. HER2 + /PIK3CA tumors have also shown drug resistance [33,34]. It has been clearly reported that 8% of 12 breast cancers and 4% of 24 lung cancers were associated with PIK3CA somatic mutations [12,35].…”