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H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3

Oncogene volume 29, pages 5193–5203 (2010)Cite this article

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Abstract

Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K, but not E545K PI3K, markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors.

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References

  • Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S et al. (2004). The PIK3CA gene is mutated in high frequency in human breast cancers. Cancer Biol Ther 3: 772–775.

    Article  CAS  PubMed  Google Scholar 

  • Bader AG, Kang S, Vogt PK . (2006). Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103: 1475–1479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellacosa A, Feo DD, Godwin AK, Bell DW, Cheng JQ, Altomare DA et al. (1995). Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64: 280–285.

    Article  CAS  PubMed  Google Scholar 

  • Berns K, Horlings HM, Hennnessy BT, Mardiredjo M, Hiijmans EM, Beelen K et al. (2007). A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzuamab resistance in breast cancer. Cancer Cell 12: 395–402.

    Article  CAS  PubMed  Google Scholar 

  • Campbell IG, Russell SE, Choong DYH, Montgomery KG, Ciavarella ML, Hooi CSF et al. (2004). Mutation in the PIK3CA gene in ovarian and breast cancer. Cancer Res 64: 7678–7681.

    Article  CAS  PubMed  Google Scholar 

  • Cantley LC . (2002). The phosphoinositide 3-kinase pathway. Science 296: 1655–1657.

    Article  CAS  PubMed  Google Scholar 

  • Cantley LC, Yuan TL . (2008). PI3K pathway alterations in cancer: variations on a theme. Oncogene 27: 5497–5510.

    Article  PubMed  PubMed Central  Google Scholar 

  • Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM et al. (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448: 439–444.

    Article  CAS  PubMed  Google Scholar 

  • Carson JD, Van Aller G, Lehr R, Sinnamon RH, Kirkpatrick RB, Auger KR et al. (2008). Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem J 409: 519–524.

    Article  CAS  PubMed  Google Scholar 

  • Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W et al. (2008). Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68: 9221–9230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engelman JA, Cantley LC . (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7: 606–619.

    Article  CAS  PubMed  Google Scholar 

  • Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039–1043.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Echeverria C, Sellers WR . (2008). Drug discovery approaches targeting the PI3K/AKT pathway in cancer. Oncogene 27: 5511–5526.

    Article  CAS  PubMed  Google Scholar 

  • Geering B, Cutillas PR, Vanhaesebroeck B . (2007). Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits? Biochem Soc Trans 35: 199–203.

    Article  CAS  PubMed  Google Scholar 

  • Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S et al. (2008). Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118: 2609–2619.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gymnopoulos M, Elsliger M-A, Vogt PK . (2007). Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104: 5569–5574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas III CF, Hynes NE . (2003). The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 100: 8933–8938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang C-H, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW et al. (2007). The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318: 1744–1748.

    Article  CAS  PubMed  Google Scholar 

  • Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV et al. (2005). Breast-cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65: 10992–11000.

    Article  CAS  PubMed  Google Scholar 

  • Junttila TT, Akita RW, Parsons K, Fields C, Phillips GDL, Friedman LS et al. (2009). Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15: 429–440.

    Article  CAS  PubMed  Google Scholar 

  • Kang S, Bader AG, Vogt PK . (2005). Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102: 802–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karakas B, Bachman KE, Park BH . (2006). Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94: 455–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M et al. (2006). Activity of the dual kinase inhibitor lapatinib (GW572016) against HER2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66: 1630–1639.

    Article  CAS  PubMed  Google Scholar 

  • Lai Y-L, Mau B-L, Cheng W-H, Chen H-M, Chiu H-H, Tzen C-Y . (2008). PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15: 1064–1069.

    Article  PubMed  Google Scholar 

  • Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP et al. (2008). A central role of HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68: 5878–5887.

    Article  CAS  PubMed  Google Scholar 

  • Lee JY, Engelman JA, Cantley LC . (2007). Biochemistry. PI3K charges ahead. Science 317: 206–207.

    Article  CAS  PubMed  Google Scholar 

  • Lerma E, Catasus L, Gallardo A, Peiro G, Gallardo A, Peiro G et al. (2008). Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas. Virchows Arch 453: 133–139.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.

    Article  CAS  PubMed  Google Scholar 

  • Li SY, Rong M, Grieu F, Iacopetta B . (2006). PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96: 91–95.

    Article  CAS  PubMed  Google Scholar 

  • Maira SM, Stuffer F, Brueggen J, Furet P, Schnell C, Fritsch C et al. (2008). Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7: 1851–1863.

    Article  CAS  PubMed  Google Scholar 

  • Medina PJ, Goodin S . (2008). Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 30: 1426–1447.

    Article  CAS  PubMed  Google Scholar 

  • Miled N, Yan Y, Hon W-C, Perisic O, Zvelebil M, Inbar Y et al. (2007). Mechanisms of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317: 239–242.

    Article  CAS  PubMed  Google Scholar 

  • Muthuswamy SK, Li D, Lelievre S, Bissell MJ, Brugge JS . (2001). ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol 3: 785–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA et al. (2004). PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6: 117–127.

    Article  CAS  PubMed  Google Scholar 

  • Nahta R, Yu D, Huang M-C, Hortobagyi GN, Esteva FJ . (2006). Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Practice Oncol 3: 269–280.

    Article  CAS  Google Scholar 

  • Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat J-P . (2008). ErbB/HER ligands in human breast cancer, and relationships with the receptors, the biopathological features and prognosis. Ann Oncol 19: 73–80.

    Article  CAS  PubMed  Google Scholar 

  • Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA et al. (2007). Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 13: 4909–4919.

    Article  CAS  PubMed  Google Scholar 

  • Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X et al. (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65: 2554–2559.

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Diaz LA, Schmidt-Kittler O, Cummins JM, DeLong L, Cheong I et al. (2005). Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7: 561–573.

    Article  CAS  PubMed  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.

    Article  CAS  PubMed  Google Scholar 

  • Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M et al. (2008). NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68: 8022–8030.

    Article  CAS  PubMed  Google Scholar 

  • Slamon D, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 344: 783–792.

    Article  CAS  PubMed  Google Scholar 

  • Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo W-L, Davies M et al. (2008). An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68: 6084–6091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai M-S, Shanmon-Taylor LA, Mehmi I, Tang CK, Lupu R . (2003). Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22: 761–768.

    Article  CAS  PubMed  Google Scholar 

  • Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL . (2004). Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem 279: 24505–24513.

    Article  CAS  PubMed  Google Scholar 

  • Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ et al. (2009). AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16: 21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.

    Article  CAS  PubMed  Google Scholar 

  • Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S et al. (2006). HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10: 25–38.

    Article  PubMed  Google Scholar 

  • Wang SE, Xiang B, Guix M, Olivares MG, Parker J, Chung CH et al. (2008). Transforming growth factor beta engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Mol Cell Biol 28: 5605–5620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL . (2002). Herceptin-induced inhibition of phosphatidylinositol-3 kinase and AKT is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62: 4132–4141.

    CAS  PubMed  Google Scholar 

  • Yarden Y, Sliwkowski MX . (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137.

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Vogt PK . (2008). Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105: 2652–2657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr H Shelton Earp III and Dr Carlos Garcia-Echeverria for providing the HER4 antibody and NVP-BEZ235, respectively. This work was supported by R01 CA80195 (CLA), ACS Clinical Research Professorship Grant CRP-07-234 (CLA), Breast Cancer Specialized Program of Research Excellence (SPORE) P50 CA98131 and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485.

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  1. S E Wang

    Present address: 5Current address: Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.,

Authors and Affiliations

  1. Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    A Chakrabarty, B N Rexer & C L Arteaga

  2. Department of Cancer Biology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    S E Wang, R S Cook & C L Arteaga

  3. Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    R S Cook & C L Arteaga

  4. Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA

    J A Engelman

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Chakrabarty, A., Rexer, B., Wang, S. et al. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29, 5193–5203 (2010). https://doi.org/10.1038/onc.2010.257

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