Molecular Biology of Breast Cancer

Maria M Caffarel, University of Cambridge, Cambridge, UK
Sara Pensa, University of Cambridge, Cambridge, UK
Julie A Wickenden, University of Cambridge, Cambridge, UK
Christine J Watson, University of Cambridge, Cambridge, UK

Published online: March 2011

DOI: 10.1002/9780470015902.a0023164

Breast cancer is a common disease affecting approximately 1 in 10 women at some time in their lives. Moreover, it is not a single disease but is characterised by distinct pathological types with different clinical outcomes. In the past decade, considerable progress has been made in understanding these different cancer subtypes at the molecular level. In particular, global gene expression studies have identified five predominant subtypes that have unique expression signatures. Unlike many other cancers, where a hierarchy of genetic mutations that leads to tumorigenesis has been identified, breast tumours have diverse genetic mutations that affect a variety of signalling pathways. The recent discovery of micro ribonucleic acids (microRNAs) and their role in tumour metastasis has opened up a whole new area of research. Although some highly successful treatments have been developed, the challenge for the future is the development of individualised therapies that are specific to each patient's tumour type.

Key Concepts:

  • Breast cancer is a heterogeneous disease characterised by distinct pathological types with different outcomes.
  • Breast tumours have diverse genetic mutations that affect a variety of signalling pathways.
  • Breast tumours can be classified into different subgroups according to their molecular expression profiles.
  • It is not clear whether specific molecular pathways establish the subtype of breast cancer or whether different cell types become transformed and give rise to each tumour subtype.
  • Breast cancer patients would benefit from individual therapeutic regimens designed to treat their particular type of cancer.

Keywords: mammary gland; breast cancer; cell of origin; molecular classification; individualised therapy

Figure 1. The human mammary gland. (a) Schematic representation of the human mammary gland, comprising ducts, alveoli, adipose tissue and connective tissue, as indicated. (b) Section of a normal duct (top) and of a ductal carcinoma in situ (DCIS, bottom).
Figure 2. Adult mouse mammary gland. (a) Schematic representation of the structure and cellular composition of the mammary gland. (b) Immunofluorescence staining of representative sections of the mammary gland showing the markers expressed in the basal (right) and in the luminal (left) layers of the ducts/alveoli. Whole mounts of a virgin (left) and a pregnant (right) mouse mammary gland are also shown.
Figure 3. Model of the differentiation hierarchy in the mammary gland. Some of the markers used to distinguish some of the populations are indicated.
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 References
    Al-Hajj M, Wicha MS, Benito-Hernandez A et al. (2003) Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the USA 100(7): 3983–3988.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573): 1655–1657.
    Chou J, Provot S and Werb Z (2010) GATA3 in development and cancer differentiation: cells GATA have it!. Journal of Cell Physiology 222(1): 42–49.
    Curigliano G, Locatelli M, Fumagalli L et al. (2009) Immunizing against breast cancer: a new swing for an old sword. Breast 18(suppl. 3): S51–S54.
    Deome KB, Faulkin LJ Jr, Bern HA et al. (1959) Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Research 19(5): 515–520.
    Dumont N, Crawford YG, Sigaroudinia M et al. (2009) Human mammary cancer progression model recapitulates methylation events associated with breast premalignancy. Breast Cancer Research 11(6): R87.
    Eirew P, Stingl J, Raouf A et al. (2008) A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nature Medicine 14(12): 1384–1389.
    Ginestier C, Hur MH, Charafe-Jauffret E et al. (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5): 555–567.
    Griffiths AB, Burchell J, Gendler S et al. (1987) Immunological analysis of mucin molecules expressed by normal and malignant mammary epithelial cells. International Journal of Cancer 40(3): 319–327.
    Haffner MC, Berlato C and Doppler W (2006) Exploiting our knowledge of NF-kappaB signaling for the treatment of mammary cancer. Journal of Mammary Gland Biology and Neoplasia 11(1): 63–73.
    Harris TJ and McCormick F (2010) The molecular pathology of cancer. Nature Reviews. Clinical Oncology 7(5): 251–265.
    Herschkowitz JI, Simin K, Weigman VJ et al. (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biology 8(5): R76.
    Jaini R, Kesaraju P, Johnson JM et al. (2010) An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nature Medicine 16(7): 799–803.
    Jeselsohn R, Brown NE, Arendt L et al. (2010) Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell 17(1): 65–76.
    Klaus A and Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nature Reviews. Cancer 8(5): 387–398.
    Lim E, Vaillant F, Wu D et al. (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Medicine 15(8): 907–913.
    Lobo NA, Shimono Y, Qian D et al. (2007) The biology of cancer stem cells. Annual Review of Cell and Developmental Biology 23: 675–699.
    Moasser MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26(45): 6469–6487.
    Molyneux G, Geyer FC, Magnay FA et al. (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3): 403–417.
    Perou CM, Sorlie T, Eisen MB et al. (2000) Molecular portraits of human breast tumours. Nature 406(6797): 747–752.
    Polyak K (2007) Breast cancer: origins and evolution. Journal of Clinical Investigation 117(11): 3155–3163.
    Prat A, Parker JS, Karginova O et al. (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Research 12(5): R68.
    Shackleton M, Vaillant F, Simpson KJ et al. (2006) Generation of a functional mammary gland from a single stem cell. Nature 439(7072): 84–88.
    Shipitsin M, Campbell LL, Argani P et al. (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3): 259–273.
    Sleeman KE, Kendrick H, Robertson D et al. (2007) Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. Journal of Cell Biology 176(1): 19–26.
    Smalley MJ, Titley J and O'Hare MJ (1998) Clonal characterization of mouse mammary luminal epithelial and myoepithelial cells separated by fluorescence-activated cell sorting. In vitro. In Vitro Cellular & Developmental Biology. Animal 34(9): 711–721.
    Sorlie T, Perou CM, Tibshirani R et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences of the USA 98(19): 10869–10874.
    Sorlie T, Tibshirani R, Parker J et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences of the USA 100(14): 8418–8423.
    Sotiriou C, Neo SY, McShane LM et al. (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proceedings of the National Academy of Sciences of the USA 100(18): 10393–10398.
    Sotiriou C and Piccart MJ (2007) Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nature Reviews. Cancer 7(7): 545–553.
    Stingl J (2009) Detection and analysis of mammary gland stem cells. Journal of Pathology 217(2): 229–241.
    Stingl J and Caldas C (2007) Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nature Reviews. Cancer 7(10): 791–799.
    Stingl J, Eaves CJ, Zandieh I et al. (2001) Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Research and Treatment 67(2): 93–109.
    Stingl J, Eirew P, Ricketson I et al. (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439(7079): 993–997.
    Taddei I, Deugnier MA, Faraldo MM et al. (2008) Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nature Cell Biology 10(6): 716–722.
    book Tavassoli FA and Devilee P (eds) (2003) "Pathology and Genetics Tumours of the Breast and Female Genital Organs". WHO Classification of Tumours, pp. 13–59. Lyon: Lyon Press.
    Valastyan S, Reinhardt F, Benaich N et al. (2009) A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 137(6): 1032–1046.
    Vargo-Gogola T and Rosen JM (2007) Modelling breast cancer: one size does not fit all. Nature Reviews. Cancer 7(9): 659–672.
    van ‘t Veer LJ, Dai H, van de Vijver MJ et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871): 530–536.
    Villadsen R, Fridriksdottir AJ, Ronnov-Jessen L et al. (2007) Evidence for a stem cell hierarchy in the adult human breast. Journal of Cell Biology 177(1): 87–101.
    Visvader JE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes & Development 23(22): 2563–2577.
    Wang Y, Klijn JG, Zhang Y et al. (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460): 671–679.
    Weigelt B and Reis-Filho JS (2009) Histological and molecular types of breast cancer: is there a unifying taxonomy? Nature Reviews. Clinical Oncology 6(12): 718–730.
    Wickenden JA and Watson CJ (2010) Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts. Breast Cancer Research 12(2): 202.
    Yu H, Pardoll D and Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Reviews. Cancer 9(11): 798–809.
    Yu Q, Geng Y and Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411(6841): 1017–1021.
 Further Reading
    Sotiriou C and Desmedt C (2006) Gene expression profiling in breast cancer. Annals of Oncology 17(suppl. 10): x259–x262.

Related Sub-Topics:

Cell Biology of Cancer | Cancer Genetics | Gene Expression Profiling of Genetic Disease | Noncoding RNA | DNA Damage and Repair
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Article Title: Molecular Biology of Breast Cancer
 
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Caffarel, Maria M, Pensa, Sara, Wickenden, Julie A, and Watson, Christine J(Mar 2011) Molecular Biology of Breast Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023164]