Abstract
The majority of solid tumors, including breast, prostate, colon, and lung cancers, originate from normal epithelium. The differentiation programs of epithelial cells dictate their specialized function, including their cell shape, polarity, arrangement, and architecture. In epithelial malignancies, the differentiation status of a primary tumor strongly predicts its capacity for metastasis formation and resistance to chemotherapeutic agents (Bloom and Richardson 1957; Contesso et al. 1987). Poorly differentiated neoplasias typically harbor higher rates of distant metastasis formation and thus carry poorer prognoses compared to their well-differentiated counterparts. The loss of tumor differentiation is one of the central hallmarks of malignant progression, the process by which a primary tumor acquires the capacity for dissemination and metastasis (Gupta and Massague 2006; Hanahan and Weinberg 2000). Genetic studies in mice and other organisms have uncovered the molecular basis for epithelial differentiation, which is shedding light on the pathogenesis of epithelial malignancies and revealing new strategies for cancer therapeutic development.
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References
Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, Busslinger M, McCright B, Gridley T, Flavell RA (2007) Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27:89–99
Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J et al (2007) Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9:201–209
Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326
Bertucci F, Houlgatte R, Benziane A, Granjeaud S, Adelaide J, Tagett R, Loriod B, Jacquemier J, Viens P, Jordan B et al (2000) Gene expression profiling of primary breast carcinomas using arrays of candidate genes. Hum Mol Genet 9:2981–2991
Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377
Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat ML, Oakes SR, Lindeman GJ, Visvader JE (2008) Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3:429–441
Buono KD, Robinson GW, Martin C, Shi S, Stanley P, Tanigaki K, Honjo T, Hennighausen L (2006) The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy. Dev Biol 293:565–580
Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR et al (2005) Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122:33–43
Chepko G, Smith GH (1997) Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 29:239–253
Contesso G, Mouriesse H, Friedman S, Genin J, Sarrazin D, Rouesse J (1987) The importance of histologic grade in long-term prognosis of breast cancer: a study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy. J Clin Oncol 5:1378–1386
Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh CH, Minokawa T, Amore G, Hinman V, Arenas-Mena C et al (2002) A genomic regulatory network for development. Science 295:1669–1678
Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI, Dickson R, Furth P, Hunter K, Kucherlapati R et al (2002) Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci USA 99:6967–6972
Dydensborg AB, Rose AA, Wilson BJ, Grote D, Paquet M, Giguere V, Siegel PM, Bouchard M (2009) GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene 28:2634–2642
Eeckhoute J, Keeton EK, Lupien M, Krum SA, Carroll JS, Brown M (2007) Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Res 67:6477–6483
Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS (2007) Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27:100–110
Finnegan TJ, Carey LA (2007) Gene-expression analysis and the basal-like breast cancer subtype. Future Oncol 3:55–63
Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS (2001) Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 61:5979–5984
Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695
Gusterson B (2009) Do ‘basal-like’ breast cancers really exist? Nature reviews 9:128–134
Guy CT, Cardiff RD, Muller WJ (1992a) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992b) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89:10578–10582
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8:R76
Hoch RV, Thompson DA, Baker RJ, Weigel RJ (1999) GATA-3 is expressed in association with estrogen receptor in breast cancer. Int J Cancer 84:122–128
Jenssen TK, Kuo WP, Stokke T, Hovig E (2002) Associations between gene expressions in breast cancer and patient survival. Hum Genet 111:411–420
Kenney NJ, Smith GH, Lawrence E, Barrett JC, Salomon DS (2001) Identification of stem cell units in the terminal end bud and duct of the mouse mammary gland. J Biomed Biotechnol 1:133–143
Kordon EC, Smith GH (1998) An entire functional mammary gland may comprise the progeny from a single cell. Development 125:1921–1930
Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ, Pai SY, Ho IC, Werb Z (2008a) GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13:141–152
Kouros-Mehr H, Kim JW, Bechis SK, Werb Z (2008b) GATA-3 and the regulation of the mammary luminal cell fate. Curr Opin Cell Biol 20:164–170
Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (2006) GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127:1041–1055
Kouros-Mehr H, Werb Z (2006) Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 235:3404–3412
Laganiere J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguere V (2005) From the cover: location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc Natl Acad Sci USA 102:11651–11656
Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K et al (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313
Levine M, Davidson EH (2005) Gene regulatory networks for development. Proc Natl Acad Sci USA 102:4936–4942
Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440
Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W, Carroll JS, Liu XS, Brown M (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132:958–970
Mehra R, Varambally S, Ding L, Shen R, Sabel MS, Ghosh D, Chinnaiyan AM, Kleer CG (2005) Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. Cancer Res 65:11259–11264
NCCN. (2009). National Comprehensive Cancer Network. Clinlcal practice guidelines in oncology. Breast Cancer 1
Nishiyama A, Xin L, Sharov AA, Thomas M, Mowrer G, Meyers E, Piao Y, Mehta S, Yee S, Nakatake Y et al (2009) Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell 5:420–433
Pei XH, Bai F, Smith MD, Usary J, Fan C, Pai SY, Ho IC, Perou CM, Xiong Y (2009) CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer Cell 15:389–401
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752
Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, van Lohuizen M (2008) Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium. Curr Biol 18:1094–1099
Raouf A, Zhao Y, To K, Stingl J, Delaney A, Barbara M, Iscove N, Jones S, McKinney S, Emerman J et al (2008) Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell 3:109–118
Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE (2006) Generation of a functional mammary gland from a single stem cell. Nature 439:84–88
Sims AH, Howell A, Howell SJ, Clarke RB (2007) Origins of breast cancer subtypes and therapeutic implications. Nature clinical practice 4:516–525
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874
Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z (2006) Hormonal and local control of mammary branching morphogenesis. Differentiation 74:365–381
Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439:993–997
Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS (2000) Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290:134–138
Visvader JE, Lindeman GJ (2003) Transcriptional regulators in mammary gland development and cancer. Int J Biochem Cell Biol 35:1034–1051
Voduc D, Cheang M, Nielsen T (2008) GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol Biomarkers Prev 17:365–373
Walker E, Ohishi M, Davey RE, Zhang W, Cassar PA, Tanaka TS, Der SD, Morris Q, Hughes TR, Zandstra PW et al (2007) Prediction and testing of novel transcriptional networks regulating embryonic stem cell self-renewal and commitment. Cell Stem Cell 1:71–86
Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH (2006) A protein interaction network for pluripotency of embryonic stem cells. Nature 444:364–368
Welm BE, Dijkgraaf GJ, Bledau AS, Welm AL, Werb Z (2008) Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer. Cell Stem Cell 2:90–102
Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA (2002) Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245:42–56
Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049
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Kouros-Mehr, H. (2012). Differentiation Programs in Development and Cancer. In: Green, J., Ried, T. (eds) Genetically Engineered Mice for Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69805-2_13
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