Cancer Cell Biology

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PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality

  1. Elena López-Knowles1,
  2. Sandra A. O'Toole1,2,3,4,
  3. Catriona M. McNeil1,5,
  4. Ewan K.A. Millar1,6,7,8,
  5. Min R. Qiu1,9,
  6. Paul Crea10,
  7. Roger J. Daly1,4,
  8. Elizabeth A. Musgrove1,4,
  9. Robert L. Sutherland1,4,†,*

Article first published online: 14 AUG 2009

DOI: 10.1002/ijc.24831

Issue

International Journal of Cancer

International Journal of Cancer

Volume 126, Issue 5, pages 1121–1131, 1 March 2010

Additional Information

How to Cite

López-Knowles, E., O'Toole, S. A., McNeil, C. M., Millar, E. K.A., Qiu, M. R., Crea, P., Daly, R. J., Musgrove, E. A. and Sutherland, R. L. (2010), PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int. J. Cancer, 126: 1121–1131. doi: 10.1002/ijc.24831

Author Information

  1. 1

    Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia

  2. 2

    Department of Anatomical Pathology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

  3. 3

    Central Clinical School, University of Sydney, Sydney, NSW 2050, Australia

  4. 4

    St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia

  5. 5

    Department of Medical Oncology, Westmead Hospital, Sydney, NSW 2145, Australia

  6. 6

    Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, NSW 2217, Australia

  7. 7

    Department of Pathology, School of Medicine, University of Western Sydney, Sydney, Australia

  8. 8

    School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia

  9. 9

    Department of Anatomical Pathology, Sydpath, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia

  10. 10

    Department of Surgical Oncology, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia

  1. †

    Fax: +61-2-92958321

*Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia

Publication History

  1. Issue published online: 27 DEC 2009
  2. Article first published online: 14 AUG 2009
  3. Accepted manuscript online: 14 AUG 2009 12:00AM EST
  4. Manuscript Accepted: 3 AUG 2009
  5. Manuscript Received: 10 MAY 2009

Funded by

  • National Health and Medical Research Council of Australia (NHMRC)
  • Cancer Institute NSW, Petre Foundation, RT Hall Trust

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Keywords:

  • breast cancer;
  • PI3K;
  • PTEN;
  • prognosis;
  • basal-like phenotype

Abstract

Breast cancer is a common malignancy with current biological therapies tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may contribute to therapeutic resistance. We undertook an integrative study of mutational, copy number and expression analyses of key regulators of the PI3K pathway in a cohort of 292 invasive breast cancer patients with known treatment outcomes. The alterations identified in this cohort included PIK3CA mutations (12/168, i.e. 7%), PIK3CA copy number gain (28/209, i.e. 14%), PTEN loss (73/258, i.e. 28%) and AKT activation (62/258, i.e. 24%). Overall at least 1 parameter was altered in 72% (139/193) of primary breast cancers. PI3K pathway activation was significantly associated with ER negative (p = 0.0008) and PR negative (p = 0.006) status, high tumor grade (p = 0.032) and a “basal-like” phenotype (p = 0.01), where 92% (25/27) of tumors had an altered pathway. In univariate analysis, PI3K pathway aberrations were associated with death from breast cancer; however, this relationship was not maintained in multivariate analysis. No association was identified between an activated pathway and outcome in tamoxifen- or chemotherapy-treated patients. We concluded that >70% of breast cancers have an alteration in at least 1 component of the PI3K pathway and this might be exploited to therapeutic advantage especially in “basal-like” cancers.

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