Abstract
In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.
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References
Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al. Tumour evolution inferred by single-cell sequencing. Nature 2011; 472: 90–94.
Greaves M, Maley CC . Clonal evolution in cancer. Nature 2012; 481: 306–313.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.
Malzahn K, Mitze M, Thoenes M, Moll R . Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch 1998; 433: 119–129.
van Amerongen R, Bowman Angela N, Nusse R . Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 2012; 11: 387–400.
Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 2011; 479: 189–193.
Rios AC, Fu NY, Lindeman GJ, Visvader JE . In situ identification of bipotent stem cells in the mammary gland. Nature 2014; 506: 322–327.
Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006; 439: 993–997.
Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML et al. Generation of a functional mammary gland from a single stem cell. Nature 2006; 439: 84–88.
Rosner A, Miyoshi K, Landesman-Bollag E, Xu X, Seldin DC, Moser AR et al. Pathway pathology: histological differences between ErbB/Ras and Wnt pathway transgenic mammary tumors. Am J Pathol. 2002; 161: 1087–1097.
Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci 2003; 100: 15853–15858.
Ling H, Jolicoeur P . Notch-1 signaling promotes the cyclinD1-dependent generation of mammary tumor-initiating cells that can revert to bi-potential progenitors from which they arise. Oncogene 2013; 32: 3410–3419.
Molyneux G, Geyer FC, Magnay F-A, McCarthy A, Kendrick H, Natrajan R et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 2010; 7: 403–417.
Gastaldi S, Sassi F, Accornero P, Torti D, Galimi F, Migliardi G et al. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 2013; 32: 1428–1440.
Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012; 148: 1015–1028.
Keller PJ, Arendt LM, Skibinski A, Logvinenko T, Klebba I, Dong S et al. Defining the cellular precursors to human breast cancer. Proc Natl Acad Sci 2012; 109: 2772–2777.
Ince TA, Richardson AL, Bell GW, Saitoh M, Godar S, Karnoub AE et al. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. Cancer Cell 2007; 12: 160–170.
Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009; 15: 907–913.
Proia TA, Keller PJ, Gupta PB, Klebba I, Jones AD, Sedic M et al. Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 2011; 8: 149–163.
Youssef KK, Van Keymeulen A, Lapouge G, Beck B, Michaux C, Achouri Y et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol 2010; 12: 299–305.
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN . Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 2000; 25: 55–57.
Desai TJ, Brownfield DG, Krasnow MA . Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 2014; 507: 190–194.
Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012; 337: 730–735.
Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C . Defining the mode of tumour growth by clonal analysis. Nature 2012; 488: 527–530.
Du Z, Podsypanina K, Huang S, McGrath A, Toneff MJ, Bogoslovskaia E et al. Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. Proc Natl Acad Sci 2006; 103: 17396–17401.
Robinson GW, McKnight RA, Smith GH, Hennighausen L . Mammary epithelial cells undergo secretory differentiation in cycling virgins but require pregnancy for the establishment of terminal differentiation. Development 1995; 121: 2079–2090.
Chang TH, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM . New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res 2014; 16: R1.
Haricharan S, Dong J, Hein S, Reddy JP, Du Z, Toneff M et al. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy. eLife 2013; 2: e00996.
Toneff MJ, Du Z, Dong J, Huang J, Sinai P, Forman J et al. Somatic expression of PyMT or activated ErbB2 induces estrogen-independent mammary tumorigenesis. Neoplasia (New York, NY) 2010; 12: 718–726.
Holland EC, Li Y, Celestino J, Dai C, Schaefer L, Sawaya RA et al. Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol 2000; 157: 1031–1037.
Fluck MM, Schaffhausen BS . Lessons in signaling and tumorigenesis from polyomavirus middle T antigen. Microbiol Mol Biol Rev 2009; 73: 542–563 Table of contents.
Ichaso N, Dilworth SM . Cell transformation by the middle T-antigen of polyoma virus. Oncogene 2001; 20: 7908–7916.
Guy CT, Cardiff RD, Muller WJ . Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 1992; 12: 954–961.
Pfefferle AD, Herschkowitz JI, Usary J, Harrell JC, Spike BT, Adams JR et al. Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts. Genome Biol 2013; 14: R125.
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007; 8: R76.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182.
Revillion F, Bonneterre J, Peyrat JP . ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 1998; 34: 791–808.
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.
Reddy JP, Peddibhotla S, Bu W, Zhao J, Haricharan S, Du Y-CN et al. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proc Natl Acad Sci 2010; 107: 3728–3733.
Haricharan S, Hein SM, Dong J, Toneff MJ, Aina OH, Rao PH et al. Contribution of an alveolar cell of origin to the high-grade malignant phenotype of pregnancy-associated breast cancer. Oncogene 2013; 33: 5729–5739.
Rakha EA, Reis-Filho JS, Ellis IO . Basal-like breast cancer: a critical review. J Clin Oncol 2008; 26: 2568–2581.
Reis-Filho JS, Milanezi F, Steele D, Savage K, Simpson PT, Nesland JM et al. Metaplastic breast carcinomas are basal-like tumours. Histopathology 2006; 49: 10–21.
Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 2008; 68: 4674–4682.
Reddy J, Li Y . The RCAS-TVA system for introduction of oncogenes into selected somatic mammary epithelial cells in vivo. J Mammary Gland Biol Neoplasia 2009; 14: 405–409.
Acknowledgements
We thank Dr Jeffrey Rosen for critical reading of this manuscript. This work was supported in part by funds from NIH CA124820 (to YL) and U54CA149196 (to YL; PI: Stephan Wong); from DOD CDMRP BC085050 (to YL), BC112704 (to YL) and BC073703 (YL); and from the Nancy Owens Memorial Foundation (to YL); as well as by the resources from the Dan L. Duncan Cancer Center (P30CA125123) and the Lester & Sue Smith Breast Center (P50CA058183 & P50-CA186784). SMH was supported by the CPRIT Training Program (RP101499) and by NIH training award T32AG000183. ANJ was supported by NIH training award T32GM088129. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123 and S10 RR024574) and the expert assistance of Joel M. Sederstrom.
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Hein, S., Haricharan, S., Johnston, A. et al. Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress. Oncogene 35, 1461–1467 (2016). https://doi.org/10.1038/onc.2015.206
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DOI: https://doi.org/10.1038/onc.2015.206
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