Differentiation Programs in Development and Cancer



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.


Breast Cancer Mammary Gland Luminal Cell Metastasis Formation Disseminate Tumor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 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 27:89–99PubMedCrossRefGoogle Scholar
  2. 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 9:201–209PubMedCrossRefGoogle Scholar
  3. 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 125:315–326PubMedCrossRefGoogle Scholar
  4. 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 9:2981–2991PubMedCrossRefGoogle Scholar
  5. 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 11:359–377PubMedCrossRefGoogle Scholar
  6. 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 3:429–441PubMedCrossRefGoogle Scholar
  7. 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 293:565–580PubMedCrossRefGoogle Scholar
  8. 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 122:33–43PubMedCrossRefGoogle Scholar
  9. Chepko G, Smith GH (1997) Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 29:239–253PubMedCrossRefGoogle Scholar
  10. 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 5:1378–1386PubMedGoogle Scholar
  11. 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 295:1669–1678PubMedCrossRefGoogle Scholar
  12. 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 99:6967–6972PubMedCrossRefGoogle Scholar
  13. 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 28:2634–2642PubMedCrossRefGoogle Scholar
  14. 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 67:6477–6483PubMedCrossRefGoogle Scholar
  15. 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 27:100–110PubMedCrossRefGoogle Scholar
  16. Finnegan TJ, Carey LA (2007) Gene-expression analysis and the basal-like breast cancer subtype. Future Oncol 3:55–63PubMedCrossRefGoogle Scholar
  17. 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 61:5979–5984PubMedGoogle Scholar
  18. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–695PubMedCrossRefGoogle Scholar
  19. Gusterson B (2009) Do ‘basal-like’ breast cancers really exist? Nature reviews 9:128–134PubMedCrossRefGoogle Scholar
  20. 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 12:954–961PubMedGoogle Scholar
  21. 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 89:10578–10582PubMedCrossRefGoogle Scholar
  22. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  23. 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:R76PubMedCrossRefGoogle Scholar
  24. Hoch RV, Thompson DA, Baker RJ, Weigel RJ (1999) GATA-3 is expressed in association with estrogen receptor in breast cancer. Int J Cancer 84:122–128PubMedCrossRefGoogle Scholar
  25. Jenssen TK, Kuo WP, Stokke T, Hovig E (2002) Associations between gene expressions in breast cancer and patient survival. Hum Genet 111:411–420PubMedCrossRefGoogle Scholar
  26. 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 1:133–143PubMedCrossRefGoogle Scholar
  27. Kordon EC, Smith GH (1998) An entire functional mammary gland may comprise the progeny from a single cell. Development 125:1921–1930PubMedGoogle Scholar
  28. 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 13:141–152PubMedCrossRefGoogle Scholar
  29. 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 20:164–170PubMedCrossRefGoogle Scholar
  30. 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 127:1041–1055PubMedCrossRefGoogle Scholar
  31. Kouros-Mehr H, Werb Z (2006) Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 235:3404–3412PubMedCrossRefGoogle Scholar
  32. 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 102:11651–11656PubMedCrossRefGoogle Scholar
  33. 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 125:301–313PubMedCrossRefGoogle Scholar
  34. Levine M, Davidson EH (2005) Gene regulatory networks for development. Proc Natl Acad Sci USA 102:4936–4942PubMedCrossRefGoogle Scholar
  35. 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 38:431–440PubMedCrossRefGoogle Scholar
  36. 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 132:958–970PubMedCrossRefGoogle Scholar
  37. 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 65:11259–11264PubMedCrossRefGoogle Scholar
  38. NCCN. (2009). National Comprehensive Cancer Network. Clinlcal practice guidelines in oncology. Breast Cancer 1Google Scholar
  39. 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 5:420–433PubMedCrossRefGoogle Scholar
  40. 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 15:389–401PubMedCrossRefGoogle Scholar
  41. 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 406:747–752PubMedCrossRefGoogle Scholar
  42. 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 18:1094–1099PubMedCrossRefGoogle Scholar
  43. 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 3:109–118PubMedCrossRefGoogle Scholar
  44. 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 439:84–88PubMedCrossRefGoogle Scholar
  45. Sims AH, Howell A, Howell SJ, Clarke RB (2007) Origins of breast cancer subtypes and therapeutic implications. Nature clinical practice 4:516–525PubMedCrossRefGoogle Scholar
  46. 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 98:10869–10874PubMedCrossRefGoogle Scholar
  47. Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z (2006) Hormonal and local control of mammary branching morphogenesis. Differentiation 74:365–381PubMedCrossRefGoogle Scholar
  48. 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 439:993–997PubMedGoogle Scholar
  49. Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS (2000) Function of GATA transcription factors in preadipocyte-adipocyte transition. Science 290:134–138PubMedCrossRefGoogle Scholar
  50. Visvader JE, Lindeman GJ (2003) Transcriptional regulators in mammary gland development and cancer. Int J Biochem Cell Biol 35:1034–1051PubMedCrossRefGoogle Scholar
  51. 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 17:365–373PubMedCrossRefGoogle Scholar
  52. 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 1:71–86PubMedCrossRefGoogle Scholar
  53. 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 444:364–368PubMedCrossRefGoogle Scholar
  54. 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 2:90–102PubMedCrossRefGoogle Scholar
  55. 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 245:42–56PubMedCrossRefGoogle Scholar
  56. Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296:1046–1049PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.GenentechSouth San FranciscoUSA

Personalised recommendations