Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer

Oncogene volume 41, pages 3445–3451 (2022)Cite this article

Subjects

Abstract

p110α is a catalytic subunit of phosphoinositide 3-kinase (PI3K), a major downstream effector of receptor tyrosine kinase ErbB2, that is amplified and overexpressed in 20–30% of breast cancers, 40% of which have an activating mutation in p110α. Despite the high frequency of PIK3CA gain-of-function mutations, their prognostic value is controversial. Here, we employ a knock-in transgenic strategy to restrict the expression of an activated form of ErbB2 and p110α kinase domain mutation (p110αHR) in the mammary epithelium. Physiological levels of transgene expression under the control of their endogenous promoters did not result in a major synergistic effect. However, tumors arising in ErbB2/p110αHR bi-genic strain metastasized to the lung with significantly reduced capacity compared to tumors expressing ErbB2 alone. The reduced metastasis was further associated with retention of the myoepithelial layer reminiscent of ductal carcinoma in situ (DCIS), a non-invasive stage of human breast cancer. Molecular and biochemical analyses revealed that these poorly metastatic tumors exhibited a significant decrease in phospho-myosin light chain 2 (MLC2) associated with cellular contractility and migration. Examination of human samples for MLC2 activity revealed a progressive increase in cellular contractility between non-invasive DCIS and invasive ductal carcinoma. Collectively, these data argue that p110αHR mutation attenuates metastatic behavior in the context of ErbB2-driven breast cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Physiological expression of p110αHR decreases ErbB2 protein levels and protects from lung metastasis.
Fig. 2: Tumors expressing p110αHR maintain DCIS pathology and strong cell-cell junctions.
Fig. 3: The p110αHR mutation impairs MLC2 activity which is important to cell contractility and motility.
Fig. 4: Progressive increase in MLC2 activity is correlated with breast cancer invasive progression.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Simond AM, Muller WJ. In vivo modeling of the EGFR family in breast cancer progression and therapeutic approaches. Adv Cancer Res. 2020;147:189–228.

    Article  CAS  Google Scholar 

  3. Czech MP. PIP2 and PIP3: complex roles at the cell surface. Cell. 2000;100:603–6.

    Article  CAS  Google Scholar 

  4. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615–75.

    Article  CAS  Google Scholar 

  5. Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999;253:239–54.

    Article  CAS  Google Scholar 

  6. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC. Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem. 1990;265:19704–11.

    Article  CAS  Google Scholar 

  7. Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, et al. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem. 1997;272:19236–41.

    Article  CAS  Google Scholar 

  8. Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, et al. Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell. 1992;70:419–29.

    Article  CAS  Google Scholar 

  9. Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol. 1998;16:1340–9.

    Article  CAS  Google Scholar 

  10. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Disco. 2014;13:140–56.

    Article  CAS  Google Scholar 

  11. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007;318:1744–8.

    Article  CAS  Google Scholar 

  12. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007;317:239–42.

    Article  CAS  Google Scholar 

  13. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene. 2008;27:5486–96.

    Article  CAS  Google Scholar 

  14. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res. 2007;13:6064–9.

    Article  CAS  Google Scholar 

  15. Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14:R28.

    Article  CAS  Google Scholar 

  16. Dumont AG, Dumont SN, Trent JC. The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chin J Cancer. 2012;31:327–34.

    Article  CAS  Google Scholar 

  17. Shimoi T, Hamada A, Yamagishi M, Hirai M, Yoshida M, Nishikawa T, et al. PIK3CA mutation profiling in patients with breast cancer, using a highly sensitive detection system. Cancer Sci. 2018;109:2558–66.

    Article  CAS  Google Scholar 

  18. Cizkova M, Dujaric ME, Lehmann-Che J, Scott V, Tembo O, Asselain B, et al. Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer. 2013;108:1807–9.

    Article  CAS  Google Scholar 

  19. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68:9221–30.

    Article  CAS  Google Scholar 

  20. Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci USA. 2000;97:3444–9.

    Article  CAS  Google Scholar 

  21. Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I, Tikoo A, et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J Clin Invest. 2012;122:553–7.

    Article  CAS  Google Scholar 

  22. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  Google Scholar 

  23. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  Google Scholar 

  24. Pandey PR, Saidou J, Watabe K. Role of myoepithelial cells in breast tumor progression. Front Biosci (Landmark Ed). 2010;15:226–36.

    Article  CAS  Google Scholar 

  25. Li YR, Yang WX. Myosins as fundamental components during tumorigenesis: diverse and indispensable. Oncotarget. 2016;7:46785–812.

    Article  Google Scholar 

  26. Koren S, Bentires-Alj M. Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors. FEBS J. 2013;280:2758–65.

    Article  CAS  Google Scholar 

  27. Adams JR, Xu K, Liu JC, Agamez NM, Loch AJ, Wong RG, et al. Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res. 2011;71:2706–17.

    Article  CAS  Google Scholar 

  28. Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y, et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet. 2007;39:338–46.

    Article  CAS  Google Scholar 

  29. Meyer DS, Brinkhaus H, Muller U, Muller M, Cardiff RD, Bentires-Alj M. Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res. 2011;71:4344–51.

    Article  CAS  Google Scholar 

  30. Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS. Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene. 1993;8:999–1008.

    CAS  PubMed  Google Scholar 

  31. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15:5049–59.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Canada Research Councils Chair in Molecular Oncology (950-2310-33), and a Foundation award from the Canadian Institutes of Health Research (CIHR-FDN-148373) (all to W.J.M.).

Author information

Author notes

  1. These authors contributed equally: Alexandra M. Simond, Tung Bui.

Authors and Affiliations

  1. Rosalind and Morris Goodman Cancer Research Institute, McGill University, Montreal, QC, Canada

    Alexandra M. Simond, Tung Bui, Dongmei Zuo, Virginie Sanguin-Gendreau, Trisha Rao & William J. Muller

  2. Department of Biochemistry, McGill University, Montreal, QC, Canada

    Alexandra M. Simond, Tung Bui & William J. Muller

  3. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Wayne A. Phillips

  4. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia

    Wayne A. Phillips

  5. Center for Comparative Medicine, University of California, Davis, CA, USA

    Robert D. Cardiff

  6. Faculty of Medicine, McGill University, Montreal, QC, Canada

    William J. Muller

Authors
  1. Alexandra M. Simond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tung Bui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dongmei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Virginie Sanguin-Gendreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Trisha Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wayne A. Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert D. Cardiff
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William J. Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: AMS, TR, WJM; investigation: AMS, TB, VS, DM; analysis: AMS, TB, RDC; resources: WAP; writing: AMS, TB, WJM; review and editing: AMS, TB, WAP, WJM; visualization: AMS, TB; funding acquisition: WJM; supervision: WJM.

Corresponding author

Correspondence to William J. Muller.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Simond, A.M., Bui, T., Zuo, D. et al. Physiological expression of PI3K H1047R mutation reveals its anti-metastatic potential in ErbB2-driven breast cancer. Oncogene 41, 3445–3451 (2022). https://doi.org/10.1038/s41388-022-02323-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02323-9

Search

Advanced search

Quick links