Breast cancer: origins and evolution
Breast cancer is not a single disease, but rather is composed of distinct subtypes associated with different clinical outcomes. Breast cancer is the leading cause of cancer-related death in women world-wide (Kamangar et al., 2006). Despite significant advances in diagnosing and treating breast cancer, several major unresolved clinical and scientific problems remain. These are related to (a) prevention (who needs it and when), (b) diagnosis (we need more specific and sensitive methods), (c) tumour progression and recurrence (what causes it and how to predict it), (d) treatment (who should be treated and how), and (e) therapeutic resistance (how to predict, prevent, and overcome it).
Resolving all these problems is complicated by the fact that breast cancer is not a single disease but is highly heterogeneous at both the molecular and clinical level (Perou et al., 2000; Sorlie et al., 2001). Comprehensive gene expression profiling of large sets of tumours by multiple independent groups and technologies have revealed five major molecular subtypes of breast cancer: basal-like, luminal A, luminal B, HER2+/ER–, and normal breast–like (Perou et al., 2000; Hu et al., 2006; Sorlie et al., 2006).
The molecular differences result in distinct clinical outcomes and responses to treatment; in general, the basal-like tumours have the worst, and luminal A-type tumours the best, prognosis (Sorlie et al., 2001). These subtypes are conserved across ethnic groups and are already evident at the ductal carcinoma in situ (DCIS) stage (Yu et al., 2004), suggesting distinct tumour progression pathways for each tumour type. Distinct cell of origin (e.g., cancer stem cells) and tumour subtype–specific genetic and epigenetic events are two possible, not necessarily mutually exclusive explanations of this extensive intra- and inter-tumoural heterogeneity.
Tumour progression can be viewed as an evolution of a large population of genetically and epigenetically distinct and unstable individuals in an ever-changing environment (Merlo et al., 2006). From this point of view, it is statistically more likely that all or the majority of tumour cells have the potential to evolve and the dominant clone can be different at different stages of tumour progression as well as before and after treatment. This hypothesis seemingly contradicts findings that the gene expression profiles of primary invasive tumours and their matched metastases (lymph node or distant) are more similar to each other than to other tumours of the same clinical and pathologic stage
Hypothetical model of breast tumour progression.
Schematic view of normal, in situ, invasive, and metastatic carcinoma progression. Normal breast ducts are composed of the basement membrane and a layer of luminal epithelial and myoepithelial cells. Cells composing the stroma include various leukocytes, fibroblasts, myofibroblasts, and endothelial cells. In in situ carcinomas the myoepithelial cells are epigenetically and phenotypically altered and their number decreases, potentially due to degradation of the basement membrane. At the same time, the number of stromal fibroblasts, myofibroblasts, lymphocytes, and endothelial cells increases. Loss of myoepithelial cells and basement membrane results in invasive carcinomas, in which tumour cells can invade surrounding tissues and can migrate to distant organs, eventually leading to metastases.
Hypothetical model of human mammary epithelial stem cell hierarchy and differentiation.
(A) Hypothetical depiction of mammary epithelial stem cells and their various progeny. A bipotential stem cell gives rise to luminal epithelial and myoepithelial cells, but the intermediary steps and their regulation are largely unknown (question marks). The model is likely to oversimplify the real situation, since there are many different types of luminal epithelial cells and both the myoepithelial and luminal cells are likely different in the ducts and alveoli. (B) Schematic picture of a normal terminal duct lobular unit with the putative location of the various stem and differentiated cells indicated. Grey line denotes the basement membrane; colour of cell types correlates with that in A. CK14, cytokeratin 14; MUC1, mucin 1
References
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Polyak, K. 2007 J Clin Invest. 2007;117(11):3155–3163. doi:10.1172/JCI33295.
Sorlie, T., et al. 2001. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. U. S. A. 98:10869-10874.
Sorlie, T., et al. 2006. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics. 7:127.
Yu, K., Lee, C.H., Tan, P.H., Tan, P. 2004. Conservation of breast cancer molecular subtypes and transcriptional patterns of tumour progression across distinct ethnic populations. Clin. Cancer Res. 10:5508-5517.