Section 4 -

Myoepithelial cells and Breast Cancer Sunil R Lakhani

Breast cancer is a heterogeneous disease with a disparate variety of histological types and a very wide spectrum of responsiveness to different treatments, making clinical management a challenge. The majority of breast carcinomas fall into the category of invasive ductal carcinoma, no special type (IDC-NST). These comprise approximately 70-80% of all breast cancers. Not surprisingly, the rest are of 'special type' and include lobular, tubular and mucinous carcinomas amongst others. It is clear that tumour grade (how closely it resembles its normal counterpart) is one of the best predictors of behaviour. Poorly differentiated grade III carcinomas are strongly associated with shorter recurrence-free and overall survival than lower grades I and II tumours. Within these groups, however, considerable heterogeneity still exists, and delineation of the most aggressive subtypes within grades would be of considerable clinical benefit. The normal breast comprises a duct-lobular system that resembles a bunch of grapes on a stalk. It is lined in its entirety by two layers of cells, an inner secretory cell which differentiates to a milk producing cell during lactation (luminal cell) and an outer contractile cell that helps to push the milk out during suckling (myoepithelial cell). It has been a dogma of breast pathology and biology that the vast majority of benign and malignant disease arises as a result of changes in the luminal/secretory cell of the duct-lobular tree. Review of the literature spanning the last 60 years including work from our own laboratory demonstrates that a proportion (2–18% of all invasive ductal carcinomas and up to 25% of grade III cancers) of these tumours express molecules which are normally seen in the myoepithelial compartment of the breast. These molecules include intermediate filaments, cytokeratin (CK) 5 and 14 and muscle components such as smooth muscle actin. Tumours exhibiting such a phenotype have been variously known as 'basal', 'basal-like' or 'tumours with basal/myoepithelial phenotype'. Recent cDNA expression profiling experiments have also identified a "basal-like" group of breast tumours based on their patterns of gene expression. Confusion has arisen as a result of the use of the term 'basal' which has become synonymous with the expression of high molecular weight 'basal keratins' as well with the myoepithelial cell. Although expression of 'basal' keratins' is seen in basal cells of stratified epithelium, in the breast, these keratins are seen in myoepithelial cells (or basal cells – since they sit on the basement membrane) as well as a small proportion of non-basal cells! Although a comprehensive characterization and consensus definition of basal tumours is lacking, work from our own laboratory as well as those of others have shown that ductal cancers that express basal/myoepithelial markers have a distinct morphology, immunophenotype, and genotype and expression profile. It has also become apparent that tumours arising in patients with BRCA1 germline mutations are also more likely to be of 'basal' type. Since medullary carcinomas are over-represented in the BRCA1 group, perhaps it is not a surprise that this special type of breast cancer is also within the spectrum of 'basal' tumours. Finally, it has become clear that the heterogeneous group of tumours referred to as metaplastic carcinomas also express 'basal' markers. The pathogenesis of such lesions appears to indicate a poor prognosis with shorter overall survival. Work from our own laboratory, however, suggests that a bad prognosis for all basal tumours is an oversimplification and that there is heterogeneity with sub groups of basal breast tumours having different behaviour. More detailed and larger studies of the sub groups of basal tumours are required to confirm the existence of basal tumour sub groups in a large population and to identify markers that may be used in histopathological diagnosis to aid patient treatment planning. As well as developing prognostic markers for diagnosis, detailed studies of the basal phenotype may lead to the identification of new targets for therapy. Data from our laboratory as well as other groups suggest that many basal tumours express high levels of EGFR. These observations need to be extended to the whole spectrum of basal breast tumours to establish whether EGFR might prove to be a therapeutic target in these cases. Selected reading Elston, C.W. and I.O. 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Reis-Filho JS, Milanezi F, Carvalho S, Simpson PT, Steele D, Savage K, Lambros MB, Pereira EM, Nesland JM, Lakhani SR, Schmitt FC. Metaplastic breast carcinomas exhibit EGFR, but not HER2, gene amplification and overexpression: immunohistochemical and chromogenic in situ hybridization analysis. Breast Cancer Res. 2005;7(6):R1028-35 Reis-Filho J, Pinheiro C, Lambros M, Milanezi F, Carvalho S, Savage K, Simpson P, Jones C, Swift S, Mackay A, Reis R, Hornick J, Pereira E, Baltazar F, Fletcher C, Ashworth A, Lakhani S, Schmitt F. EGFR amplification and lack of activating mutations in metaplastic breast carcinomas. J Pathol. 2006 (in press)