Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma

Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, cytokeratin 5/6, cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal cytokeratin 8/18 (15/18), EGFR (13/18), and cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER− and HER2−. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P<0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, cytokeratin 8/18, and cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype.

[1]  F. Rilke,et al.  Vimentin and p53 expression on epidermal growth factor receptor-positive, oestrogen receptor-negative breast carcinomas. , 1988, British Journal of Cancer.

[2]  E. Gelmann,et al.  Vimentin rather than keratin expression in some hormone-independent breast cancer cell lines and in oncogene-transformed mammary epithelial cells. , 1989, Cancer research.

[3]  G. Striker,et al.  Vimentin expression appears to be associated with poor prognosis in node-negative ductal NOS breast carcinomas. , 1990, The American journal of pathology.

[4]  M. Hendrix,et al.  Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. , 1997, The American journal of pathology.

[5]  S. Hirohashi,et al.  Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones. , 1999, Human pathology.

[6]  Christian A. Rees,et al.  Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[8]  S. Hirohashi,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. , 2000, The American journal of surgical pathology.

[9]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  O. Dietze,et al.  Co‐expression of tenascin‐C and vimentin in human breast cancer cells indicates phenotypic transdifferentiation during tumour progression: correlation with histopathological parameters, hormone receptors, and oncoproteins , 2001, The Journal of pathology.

[11]  C. Sotiriou,et al.  Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer , 2002, Breast Cancer Research.

[12]  J. Sng,et al.  Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[14]  Martin Eisenacher,et al.  Cytogenetic Alterations and Cytokeratin Expression Patterns in Breast Cancer: Integrating a New Model of Breast Differentiation into Cytogenetic Pathways of Breast Carcinogenesis , 2002, Laboratory Investigation.

[15]  R. Tibshirani,et al.  Copyright © American Society for Investigative Pathology Short Communication Expression of Cytokeratins 17 and 5 Identifies a Group of Breast Carcinomas with Poor Clinical Outcome , 2022 .

[16]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[17]  I. Andrulis,et al.  HER‐2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry , 2002, Cancer.

[18]  C. Perou,et al.  Molecular portraits and the family tree of cancer , 2002, Nature Genetics.

[19]  Van,et al.  A gene-expression signature as a predictor of survival in breast cancer. , 2002, The New England journal of medicine.

[20]  M. West,et al.  Gene expression predictors of breast cancer outcomes , 2003, The Lancet.

[21]  Philip M. Long,et al.  Breast cancer classification and prognosis based on gene expression profiles from a population-based study , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  L. Bégin,et al.  Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. , 2004, Journal of the National Cancer Institute.

[23]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[25]  S. Shousha,et al.  Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma , 2004, Modern Pathology.

[26]  William D. Foulkes,et al.  Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer , 2004 .

[27]  Wei Wang,et al.  A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. , 2004, Cancer cell.

[28]  I. Ellis,et al.  Expression of luminal and basal cytokeratins in human breast carcinoma , 2004, The Journal of pathology.

[29]  Ian O Ellis,et al.  Estrogen receptor-negative breast carcinomas: a review of morphology and immunophenotypical analysis , 2005, Modern Pathology.