Breast Cancer Research and Treatment

, Volume 122, Issue 1, pp 45–53 | Cite as

PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis

  • Mohammed A. Aleskandarany
  • Emad A. Rakha
  • Mohamed A. H. Ahmed
  • Desmond G. Powe
  • Emma C. Paish
  • R. Douglas Macmillan
  • Ian O. Ellis
  • Andrew R. Green
Preclinical study


The implications of Phosphatidylinositol 3-kinase (PIK3CA) mutations and its aberrant protein expression in breast cancer (BC) different molecular subtypes and patients’ outcome remain controversial. The aims of this study were to assess the prevalence and clinical significance of PIK3CA protein expression in BC and to determine its association with its different molecular classes. PIK3CA protein expression was assessed in a well-characterized series of early stage BC (n = 1,394) with long-term follow-up, using tissue microarrays and immunohistochemistry. Associations between PIK3CA expression and clinicopathological variables, molecular classes, and patients’ outcome were investigated. Positive PIK3CA expression was associated with poor prognostic variables including higher grade, larger size, nodal involvement, vascular invasion, and higher proliferative fraction (P < 0.001). Increased PIK3CA expression was associated with the basal-like breast cancer (BLBC) and HER2-positive classes as well as triple negative non-basal (TNnon-B) tumors (P < 0.001). The luminal class showed reduced PIK3CA expression relative to other classes. Patients with PIK3CA positive tumors had shorter BC specific and disease free survival, independent of other prognostic factors except grade. Similar associations with outcome were found when the analysis was restricted to the large luminal class of tumors. PIK3CA is an oncogenic biomarker associated with poor prognosis in BC. Although, PIK3CA over-expression was more prevalent in BLBC and HER2-positive tumors it appeared to be a marker of poor differentiation rather than of a particular subtype. Thus, targeting of PIK3CA using specific inhibitors could potentially be beneficial, particularly for patients with more aggressive poorly differentiated tumors, irrespective of their molecular subtype.


PIK3CA Immunohistochemistry Poor prognosis Breast cancer 


  1. 1.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657CrossRefPubMedGoogle Scholar
  2. 2.
    Jiang B-H, Liu L-Z (2008) PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 1784:150–158PubMedGoogle Scholar
  3. 3.
    Dillon RL, White DE, Muller WJ (2007) The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene 26:1338–1345CrossRefPubMedGoogle Scholar
  4. 4.
    Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619CrossRefPubMedGoogle Scholar
  5. 5.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JKV, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554CrossRefPubMedGoogle Scholar
  6. 6.
    Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459CrossRefPubMedGoogle Scholar
  7. 7.
    Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496CrossRefPubMedGoogle Scholar
  8. 8.
    Campbell IG, Russell SE, Choong DYH, Montgomery KG, Ciavarella ML, Hooi CSF, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA Gene in Ovarian and Breast Cancer. Cancer Res 64:7678–7681CrossRefPubMedGoogle Scholar
  9. 9.
    Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807CrossRefPubMedGoogle Scholar
  10. 10.
    Maira S-M, Stauffer F, Schnell C, García-Echeverría C (2009) PI3K inhibitors for cancer treatment: where do we stand? Biochem Soc Trans 37:265–272CrossRefPubMedGoogle Scholar
  11. 11.
    Gustin JP, Cosgrove DP, Park BH (2008) The PIK3CA gene as a mutated target for cancer therapy. Curr Cancer Drug Targets 8:733–740CrossRefPubMedGoogle Scholar
  12. 12.
    Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S (2007) Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 13:408–414CrossRefPubMedGoogle Scholar
  13. 13.
    Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She Q-B, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L, Isola J, Bendahl P-O, Rosen N, Hibshoosh H, Ringner M, Borg A, Parsons R (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104:7564–7569CrossRefPubMedGoogle Scholar
  14. 14.
    Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069CrossRefPubMedGoogle Scholar
  15. 15.
    Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom P-O, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559CrossRefPubMedGoogle Scholar
  16. 16.
    Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775PubMedCrossRefGoogle Scholar
  17. 17.
    Marty B, Maire V, Gravier E, Rigaill G, Vincent-Salomon A, Kappler M, Lebigot I, Djelti F, Tourdes A, Gestraud P, Hupe P, Barillot E, Cruzalegui F, Tucker GC, Stern MH, Thiery JP, Hickman JA, Dubois T (2008) Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res 10:R101CrossRefPubMedGoogle Scholar
  18. 18.
    Hoeflich KP, O’Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T, Zhou W, Berry L, Murray L, Amler L, Belvin M, Friedman LS, Lackner MR (2009) In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 15:4649–4664CrossRefPubMedGoogle Scholar
  19. 19.
    Buttitta F, Felicioni L, Barassi F, Martella C, Paolizzi D, Fresu G, Salvatore S, Cuccurullo F, Mezzetti A, Campani D, Marchetti A (2006) PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol 208:350–355CrossRefPubMedGoogle Scholar
  20. 20.
    Tokunaga E, Kimura Y, Mashino K, Oki E, Kataoka A, Ohno S, Morita M, Kakeji Y, Baba H, Maehara Y (2006) Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 13:137–144CrossRefPubMedGoogle Scholar
  21. 21.
    Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116:340–350CrossRefPubMedGoogle Scholar
  22. 22.
    Albasri A, Seth R, Jackson D, Benhasouna A, Crook S, Nateri AS, Chapman R, Ilyas M (2009) C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer. J Pathol 218:57–65CrossRefPubMedGoogle Scholar
  23. 23.
    McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr (1985) Estrogen receptor analyses Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721PubMedGoogle Scholar
  24. 24.
    Rakha EA, Putti TC, Abd El-Rehim DM, Paish C, Green AR, Powe DG, Lee AH, Robertson JF, Ellis IO (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208:495–506CrossRefPubMedGoogle Scholar
  25. 25.
    Rakha EA, El-Sayed ME, Green AR, Paish EC, Powe DG, Gee J, Nicholson RI, Lee AH, Robertson JF, Ellis IO (2007) Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. J Clin Oncol 25:4772–4778CrossRefPubMedGoogle Scholar
  26. 26.
    Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:7252–7259CrossRefPubMedGoogle Scholar
  27. 27.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874CrossRefPubMedGoogle Scholar
  28. 28.
    Elston CW (2005) Classification and grading of invasive breast carcinoma. Verh Dtsch Ges Pathol 89:35–44PubMedGoogle Scholar
  29. 29.
    Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO, Lee AH (2009) The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast. Eur J Cancer 45:1780–1787CrossRefPubMedGoogle Scholar
  30. 30.
    Thompson JE, Thompson CB (2004) Putting the Rap on Akt. J Clin Oncol 22:4217–4226CrossRefPubMedGoogle Scholar
  31. 31.
    Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, El-Sayed ME, Benhasouna A, Brunet JS, Akslen LA, Evans AJ, Blamey R, Reis-Filho JS, Foulkes WD, Ellis IO (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15:2302–2310CrossRefPubMedGoogle Scholar
  32. 32.
    Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091CrossRefPubMedGoogle Scholar
  33. 33.
    Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY (2008) PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15:1064–1069CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Mohammed A. Aleskandarany
    • 1
    • 2
  • Emad A. Rakha
    • 3
  • Mohamed A. H. Ahmed
    • 1
    • 5
  • Desmond G. Powe
    • 1
  • Emma C. Paish
    • 3
  • R. Douglas Macmillan
    • 4
  • Ian O. Ellis
    • 1
  • Andrew R. Green
    • 1
  1. 1.Division of Pathology, School of Molecular Medical SciencesUniversity of Nottingham, Queen’s Medical CentreNottinghamUK
  2. 2.Pathology Department, Faculty of MedicineMenoufyia UniversityMenoufyiaEgypt
  3. 3.Department of PathologyNottingham University Hospitals NHS TrustNottinghamUK
  4. 4.Breast InstituteNottingham University Hospitals NHS TrustNottinghamUK
  5. 5.Pathology Department, Faculty of MedicineSuez Canal UniversityIsmailiaEgypt

Personalised recommendations