Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling

Christian D. Young, Adam D. Pfefferle, Philip Owens, María G. Kuba, Brent N. Rexer, Justin M. Balko, Violeta Sánchez, Hailing Cheng, Charles M. Perou, Jean J. Zhao, Rebecca S. Cook, Carlos L. Arteaga

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Mutations in PIK3CA, the gene encoding the p110a catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110a via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CAmediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CAH1047R-expressing tumors. However, the p110a-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110a and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CAH1047R. These data suggest that PIK3CAH1047R-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110a and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

Original languageEnglish (US)
Pages (from-to)4075-4085
Number of pages11
JournalCancer research
Volume73
Issue number13
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Young, C. D., Pfefferle, A. D., Owens, P., Kuba, M. G., Rexer, B. N., Balko, J. M., Sánchez, V., Cheng, H., Perou, C. M., Zhao, J. J., Cook, R. S., & Arteaga, C. L. (2013). Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer research, 73(13), 4075-4085. https://doi.org/10.1158/0008-5472.CAN-12-4579