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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Nature Genetics volume 40, pages 102–107 (2008)Cite this article

Abstract

Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1,2,3. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype3,4,5; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair.

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Figure 1: IHC analysis of basal-like phenotype markers in Pten+/− mouse mammary tumors.
Figure 2: Immunohistochemical analysis of PTEN and CK5/14 basal-like phenotype markers in 297 non-hereditary human breast carcinomas.
Figure 3: PTEN status in human BRCA1-mutant hereditary breast cancers.
Figure 4: Gross PTEN mutations in BRCA1-mutant human cell lines and xenografts.
Figure 5: Gross PTEN mutations in five BRCA1-mutant breast tumor biopsies in vivo.

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References

  1. Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  Google Scholar 

  2. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).

    Article  CAS  Google Scholar 

  3. Silva, L.D., Clarke, C. & Lakhani, S.R. Basal-like breast cancer. J. Clin. Pathol. doi:10.1136/jcp.2006.041731 (published online 11 May 2007).

  4. Sorlie, T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. USA 100, 8418–8423 (2003).

    Article  CAS  Google Scholar 

  5. Turner, N.C. & Reis-Filho, J.S. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25, 5846–5853 (2006).

    Article  CAS  Google Scholar 

  6. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  7. Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).

    Article  CAS  Google Scholar 

  8. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  Google Scholar 

  9. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  Google Scholar 

  10. Jasin, M. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21, 8981–8993 (2002).

    Article  CAS  Google Scholar 

  11. Puc, J. et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7, 193–204 (2005).

    Article  CAS  Google Scholar 

  12. Baker, S.J. PTEN enters the nuclear age. Cell 128, 25–28 (2007).

    Article  CAS  Google Scholar 

  13. Janzen, V. & Scadden, D.T. Stem cells: good, bad and reformable. Nature 441, 418–419 (2006).

    Article  CAS  Google Scholar 

  14. Saal, L.H. et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc. Natl. Acad. Sci. USA 104, 7564–7569 (2007).

    Article  CAS  Google Scholar 

  15. Saal, L.H. et al. 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 (2005).

    Article  CAS  Google Scholar 

  16. Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 96, 1563–1568 (1999).

    Article  CAS  Google Scholar 

  17. Laakso, M., Loman, N., Borg, A. & Isola, J. Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod. Pathol. 18, 1321–1328 (2005).

    Article  CAS  Google Scholar 

  18. Tomlinson, G.E. et al. Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. Cancer Res. 58, 3237–3242 (1998).

    CAS  PubMed  Google Scholar 

  19. Elstrodt, F. et al. BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res. 66, 41–45 (2006).

    Article  CAS  Google Scholar 

  20. Neve, R.M. et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10, 515–527 (2006).

    Article  CAS  Google Scholar 

  21. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  Google Scholar 

  22. Giovanella, B.C., Stehlin, J.S. & Williams, L.J. Jr. Heterotransplantation of human malignant tumors in 'nude' thymusless mice. II. Malignant tumors induced by injection of cell cultures derived from human solid tumors. J. Natl. Cancer Inst. 52, 921–930 (1974).

    Article  CAS  Google Scholar 

  23. Greenblatt, M.S., Chappuis, P.O., Bond, J.P., Hamel, N. & Foulkes, W.D. TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution. Cancer Res. 61, 4092–4097 (2001).

    CAS  PubMed  Google Scholar 

  24. Evers, B. & Jonkers, J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25, 5885–5897 (2006).

    Article  CAS  Google Scholar 

  25. Weinstein, I.B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    Article  CAS  Google Scholar 

  26. Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  CAS  Google Scholar 

  27. Loman, N., Johannsson, O., Kristoffersson, U., Olsson, H. & Borg, A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J. Natl. Cancer Inst. 93, 1215–1223 (2001).

    Article  CAS  Google Scholar 

  28. Jonsson, G. et al. High-resolution genomic profiles of breast cancer cell lines assessed by tiling BAC array comparative genomic hybridization. Genes Chromosom. Cancer 46, 543–558 (2007).

    Article  Google Scholar 

  29. Staaf, J. et al. Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2 and MLH1 using zoom-in array CGH. Hum. Mutat. (in the press).

  30. Saal, L.H. et al. BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data. Genome Biol. 3 SOFTWARE0003 (2002).

Download references

Acknowledgements

We thank the patients whose contributions made this work possible. We thank B. Giovanella (Stehlin Foundation for Cancer Research) for breast cancer xenografts; J. Valcich, L. Tellhed and C. Strand for technical support; and R. Szalasny for administrative assistance. We regret our inability to cite all references germane to this work owing to space limitations. Funding was provided in part by US National Institutes of Health Scientist training grant 5T32 GM07367-29 (L.H.S.); grants CA082783 and CA097403 (R.P.); Department of Defense Breast Cancer Research Program Era of Hope Award BC061955 (S.K.G.-S.); the Avon Foundation (H.H., R.P.); the OctoberWoman Foundation (R.P.); the Swedish Cancer Society, Mrs. Berta Kamprad Foundation, Gunnar Nilsson Cancer Foundation, and Ingabritt and Arne Lundberg Foundation (Å.B.); and the Knut and Alice Wallenberg Foundation via the SWEGENE program (M.K., Å.B.).

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Author notes

  1. Ramon Parsons and Åke Borg: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, 10032, New York, USA

    Lao H Saal, Sofia K Gruvberger-Saal, Matthew Maurer, Susan Koujak, Thomas Ludwig, Vundavalli VVS Murty & Ramon Parsons

  2. College of Physicians and Surgeons, Columbia University, New York, 10032, New York, USA

    Lao H Saal

  3. Division of Oncology, Department of Clinical Sciences, Lund University, 22185, Lund, Sweden

    Camilla Persson, Kristina Lövgren, Johan Staaf, Göran Jönsson, Karolina Holm, Johan Vallon-Christersson, Håkan Olsson & Åke Borg

  4. Department of Pathology, Seinäjoki Central Hospital, 60220, Seinäjoki, Finland

    Mervi Jumppanen

  5. Institute of Medical Technology, University of Tampere, 33014, Tampere, Finland

    Mervi Jumppanen & Jorma Isola

  6. Department of Biochemistry, Columbia University, New York, 10032, New York, USA

    Maira M Pires

  7. Department of Medicine, Columbia University, New York, 10032, New York, USA

    Matthew Maurer & Ramon Parsons

  8. Department of Pathology, Columbia University, New York, 10032, New York, USA

    Shivakumar Subramaniyam, Thomas Ludwig, Matthias Szabolcs, Vundavalli VVS Murty, Hanina Hibshoosh & Ramon Parsons

  9. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, 10032, New York, USA

    Tao Su, Hanina Hibshoosh & Ramon Parsons

  10. Pathology Unit, Mediterranean Institute of Oncology, 95029, Catania, Italy

    Lorenzo Memeo

  11. Karmanos Cancer Institute, Wayne State University, Detroit, 48201, Michigan, USA

    Stephen P Ethier

  12. Department of Theoretical Physics, Computational Biology and Biological Physics, Lund University, 22362, Lund, Sweden

    Morten Krogh

  13. Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, 22185, Lund, Sweden

    Åke Borg

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  1. Lao H Saal
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Contributions

L.H.S., S.K.G.-S., R.P. and Å.B conceived and designed the study; L.H.S., S.K.G.-S., J.S., G.J., K.H., S.K., J.V.-C., H.O., T.S., L.M., S.P.E., H.H., R.P. and Å.B. collected the samples; L.H.S., K.L., M.J., L.M., T.L., M.S., J.I. and H.H. performed and analyzed immunohistochemistry experiments; L.H.S. and C.P. designed and performed methylation analyses; L.H.S., C.P., M.M. and K.H. performed nucleotide sequencing experiments; L.H.S., J.S., G.J. and K.H. performed and analyzed aCGH experiments; L.H.S., M.M.P., S.S. and V.V.V.S.M. designed and performed FISH experiments; L.H.S., S.K.G.-S. and M.K. performed statistical analyses; R.P. and Å.B. supervised the study; and L.H.S. wrote the paper with assistance from R.P. and Å.B. and input from all coauthors.

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Correspondence to Ramon Parsons.

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Saal, L., Gruvberger-Saal, S., Persson, C. et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet 40, 102–107 (2008). https://doi.org/10.1038/ng.2007.39

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