Activating PIK3CA mutations induce an epidermal growth factor receptor (EGFR)/extracellular signal-regulated Kinase (ERK) paracrine signaling axis in basal-like breast cancer

Christian D. Young, Lisa J. Zimmerman, Daisuke Hoshino, Luigi Formisano, Ariella B. Hanker, Michael L. Gatza, Meghan M. Morrison, Preston D. Moore, Corbin A. Whitwell, Bhuvanesh Dave, Thomas Stricker, Neil E. Bhola, Grace O. Silva, Premal Patel, Dana M. Brantley-Sieders, Maren Levin, Marina Horiates, Norma A. Palma, Kai Wang, Philip J. StephensCharles M. Perou, Alissa M. Weaver, Joyce A. O'Shaughnessy, Jenny C. Chang, Ben Ho Park, Daniel C. Liebler, Rebecca S. Cook, Carlos L. Arteaga

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.

Original languageEnglish (US)
Pages (from-to)1959-1976
Number of pages18
JournalMolecular and Cellular Proteomics
Volume14
Issue number7
DOIs
StatePublished - Jan 1 2015

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Paracrine Communication
Extracellular Signal-Regulated MAP Kinases
Epidermal Growth Factor Receptor
Breast Neoplasms
Mutation
Phosphatidylinositols
Tumors
Proteins
Phosphotransferases
Cells
Breast
1-Phosphatidylinositol 4-Kinase
Military electronic countermeasures
Epithelial Cells
Gene encoding
Liquid chromatography
Cell Surface Receptors
Mass spectrometry
Cell Line
Growth Inhibitors

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

Cite this

Activating PIK3CA mutations induce an epidermal growth factor receptor (EGFR)/extracellular signal-regulated Kinase (ERK) paracrine signaling axis in basal-like breast cancer. / Young, Christian D.; Zimmerman, Lisa J.; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B.; Gatza, Michael L.; Morrison, Meghan M.; Moore, Preston D.; Whitwell, Corbin A.; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E.; Silva, Grace O.; Patel, Premal; Brantley-Sieders, Dana M.; Levin, Maren; Horiates, Marina; Palma, Norma A.; Wang, Kai; Stephens, Philip J.; Perou, Charles M.; Weaver, Alissa M.; O'Shaughnessy, Joyce A.; Chang, Jenny C.; Park, Ben Ho; Liebler, Daniel C.; Cook, Rebecca S.; Arteaga, Carlos L.

In: Molecular and Cellular Proteomics, Vol. 14, No. 7, 01.01.2015, p. 1959-1976.

Research output: Contribution to journalArticle

Young, CD, Zimmerman, LJ, Hoshino, D, Formisano, L, Hanker, AB, Gatza, ML, Morrison, MM, Moore, PD, Whitwell, CA, Dave, B, Stricker, T, Bhola, NE, Silva, GO, Patel, P, Brantley-Sieders, DM, Levin, M, Horiates, M, Palma, NA, Wang, K, Stephens, PJ, Perou, CM, Weaver, AM, O'Shaughnessy, JA, Chang, JC, Park, BH, Liebler, DC, Cook, RS & Arteaga, CL 2015, 'Activating PIK3CA mutations induce an epidermal growth factor receptor (EGFR)/extracellular signal-regulated Kinase (ERK) paracrine signaling axis in basal-like breast cancer', Molecular and Cellular Proteomics, vol. 14, no. 7, pp. 1959-1976. https://doi.org/10.1074/mcp.M115.049783
Young, Christian D. ; Zimmerman, Lisa J. ; Hoshino, Daisuke ; Formisano, Luigi ; Hanker, Ariella B. ; Gatza, Michael L. ; Morrison, Meghan M. ; Moore, Preston D. ; Whitwell, Corbin A. ; Dave, Bhuvanesh ; Stricker, Thomas ; Bhola, Neil E. ; Silva, Grace O. ; Patel, Premal ; Brantley-Sieders, Dana M. ; Levin, Maren ; Horiates, Marina ; Palma, Norma A. ; Wang, Kai ; Stephens, Philip J. ; Perou, Charles M. ; Weaver, Alissa M. ; O'Shaughnessy, Joyce A. ; Chang, Jenny C. ; Park, Ben Ho ; Liebler, Daniel C. ; Cook, Rebecca S. ; Arteaga, Carlos L. / Activating PIK3CA mutations induce an epidermal growth factor receptor (EGFR)/extracellular signal-regulated Kinase (ERK) paracrine signaling axis in basal-like breast cancer. In: Molecular and Cellular Proteomics. 2015 ; Vol. 14, No. 7. pp. 1959-1976.
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abstract = "Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.",
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AU - Hoshino, Daisuke

AU - Formisano, Luigi

AU - Hanker, Ariella B.

AU - Gatza, Michael L.

AU - Morrison, Meghan M.

AU - Moore, Preston D.

AU - Whitwell, Corbin A.

AU - Dave, Bhuvanesh

AU - Stricker, Thomas

AU - Bhola, Neil E.

AU - Silva, Grace O.

AU - Patel, Premal

AU - Brantley-Sieders, Dana M.

AU - Levin, Maren

AU - Horiates, Marina

AU - Palma, Norma A.

AU - Wang, Kai

AU - Stephens, Philip J.

AU - Perou, Charles M.

AU - Weaver, Alissa M.

AU - O'Shaughnessy, Joyce A.

AU - Chang, Jenny C.

AU - Park, Ben Ho

AU - Liebler, Daniel C.

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