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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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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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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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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DOI: https://doi.org/10.1038/ng.2007.39
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