New Frontiers in Breast Pathology
Moderator: Dr. Sunil Lakhani
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.
- Elston, C.W. and I.O. Ellis, Pathological prognostic factors in breast cancer.
I. The value of histological grade in breast cancer: experience from a large study with long-term
follow-up. Histopathology, 1991. 19(5): p. 403-10.
- Gusterson, B.A., et al., Distribution of myoepithelial cells and basement
membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Res,
1982. 42(11): p. 4763-70.
- Dairkee, S.H., et al., Monoclonal antibody that defines human
myoepithelium. Proc Natl Acad Sci U S A, 1985. 82(21): p. 7409-13.
- Dairkee, S.H., et al., Immunolocalization of a human basal epithelium specific
keratin in benign and malignant breast disease. Breast Cancer Res Treat, 1987. 10(1): p. 11-20.
- Perou, C.M., et al., Molecular portraits of human breast tumours. Nature,
2000. 406(6797): p. 747-52.
- Sorlie, T., et al., Gene expression patterns of breast carcinomas distinguish
tumor subclasses with clinical implications. Proc Natl Acad Sci U S A, 2001. 98(19): p. 10869-74.
- Malzahn, K., et al., Biological and prognostic significance of stratified
epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch, 1998. 433(2): p. 119-29.
- Tsuda, H., et al., Myoepithelial differentiation in high-grade invasive ductal
carcinomas with large central acellular zones. Hum Pathol, 1999. 30(10): p. 1134-9.
- Tsuda, H., et al., Large, central acellular zones indicating myoepithelial tumor
differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain
metastases. Am J Surg Pathol, 2000. 24(2): p. 197-202.
- Sorlie, T., et al., Repeated observation of breast tumor subtypes in independent
gene expression data sets. Proc Natl Acad Sci U S A, 2003. 100(14):
- van de Rijn, M., et al., Expression of cytokeratins 17 and 5 identifies a group
of breast carcinomas with poor clinical outcome. Am J Pathol, 2002. 161(6): p. 1991-6.
- Sotiriou, C., et al., Breast cancer classification and prognosis based on gene
expression profiles from a population-based study. Proc Natl Acad Sci U S A, 2003. 100(18): p. 10393-8.
- Jones, C., Foschini, M.P., Chaggar, R., Lu, Y.J., Wells, D., Shipley, J.M., Eusebi, V., and Lakhani,
S.R., (2000). Comparative genomic hybridization analysis of myoepithelial carcinoma of the breast. Lab
Invest. 80(6): p. 831-6.
- Jones, C., Nonni, A.V., Fulford, L., Merrett, S., Chaggar, R., Eusebi, V., and Lakhani, S.R., (2001).
CGH analysis of ductal carcinoma of the breast with basaloid/myoepithelial cell differentiation. Br J
Cancer. 85(3): p. 422-7.
- Lakhani, S.R., Van De Vijver, M.J., Jacquemier, J., Anderson, T.J., Osin, P.P., McGuffog, L., and
Easton, D.F., (2002). The pathology of familial breast cancer: predictive value of immunohistochemical
markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and
BRCA2. J Clin Oncol. 20(9): p. 2310-8.
- Jones C., Ford E., Gillett C., Ryder K., Merrett S., Reis-Filho J.S., Fulford L.G., Hanby A., Lakhani
S.R. (2004). Molecular cytogenetic identification of subgroups of grade III invasive ductal breast
carcinomas with different clinical outcomes. Clin Cancer Res 10:5988-5997.
- Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, et al. Prediction
of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer
- Jacquemier J, Padovani L, Rabayrol L, Lakhani SR, Penault-Llorca F, Denoux Y, Fiche M, Figueiro P, Maisongrosse V, Ledoussal V, Martinez Penuela J, Udvarhely
N, El Makdissi G, Ginestier C, Geneix J, Charafe-Jauffret
E, Xerri L, Eisinger F, Birnbaum D, Sobol H; European Working Group for Breast Screening Pathology; Breast
Cancer Linkage Consortium. Typical medullary breast carcinomas have a basal/myoepithelial phenotype.
J Pathol. 2005 ;207:260-8.
- 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.
- 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)