Metaplastic Breast Carcinomas Are Enriched for ALDH-1 Positive Stem Cells in Non-Glandular Elements.
Yanhong Zhang, Kathy Toy, Celina G Kleer. University of Michigan, Ann Arbor
Background: Metaplastic breast carcinomas are distinct aggressive form of breast cancers characterized by areas of non glandular differentiation, which may be squamous/spindle and/or sarcomatous. Understanding their pathogenesis would result in more effective treatments. Recent studies have shown that cancer cells undergoing epithelial to mesenchymal transition (EMT) exhibit stem cell-like characteristics and more aggressive properties. ZEB1, a potent inducer of EMT through E-cadherin transcriptional control, confers a stem cell phenotype in immortalized human mammary epithelial cells. However, the relevance of these studies to human metaplastic breast cancer has not been demonstrated. We hypothesized that metaplastic breast carcinomas may be enriched for EMT markers and express the cancer stem cell marker ALDH1.
Design: Double staining immunohistochemistry was performed to determine the expression of EMT markers E-cadherin and ZEB1; and single staining for breast cancer stem cell marker ALDH1 in 27 primary metaplastic breast carcinomas. E-cadherin expression was classified as normal (membranous staining) or aberrant (negative or reduced expression). ZEB1 staining was scored as positive (any nuclear expression) or negative, and ALDH1 staining as positive (any tumor cell with cytoplasmic staining) or negative, as previously reported.
Results: Of the 27 metaplastic breast carcinomas 20 had squamous and/or spindle areas, and 7 had heterologous elements (6 chondroid and 1 osseous). An associated glandular component was seen in 11 tumors. Detailed analysis of each individual component revealed ALDH1 positive cells in 62% of the spindle and squamous component, and in 75% of the heterologous elements. In contrast, ALDH1 positive cells were rare in the glandular component (9%), Fisher exact, p=0.0017. E-cadherin was aberrant in all metaplastic components while it was normal in the glandular areas. A significant correlation among aberrant E-cadherin, positive ZEB1 and the presence of ALDH1 positive stem cells was observed in over 90% of the spindle areas and heterologous elements (Chi Square test, p<0.05).
Conclusions: Our data show for the first time that metaplastic carcinomas are enriched for ALDH1 positive cancer stem cells, specifically in the metaplastic components, not in the glandular areas. ZEB1, an E-cadherin transcriptional repressor and inducer of EMT, may play a critical role in E-cadherin downregulation and in the increase of ALDH1 positive cancer stem cells detected in metaplastic breast carcinomas.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 1, Tuesday Afternoon