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[80] Morphological and Molecular Evolutionary Pathways of Low Grade Breast Cancers and Their Putative Precursor Lesions

T Abdel-Fatah, DG Powe, Z Hodi, JS Reis-Filho, A Lee, IO Ellis. Nottingham University, Nottingham, United Kingdom; Institute of Cancer Research, London, United Kingdom

Background: We investigated the morphological and molecular evolutionary pathways involved in the development of low grade breast cancers by studying the frequency of association and immunoprofile of putative precursor lesions including CCLs, UEH, ADH, DCIS, and LN.
Design: The frequency of invasive and pre-invasive lesions was microscopically determined in 200 low grade breast tumours comprising low grade IDC, cribriform, pure and mixed type tubular (TC), tubulolobular (TLC) and ILC classic type. Tissue microarrays containing 1100 of these lesions were immunohistochemically compared for putative tumour suppressor genes (TSGs), cell cycle regulators, proliferation and differentiation markers.
Results: Morphology: > 85% low grade IDC, cribriform, TC and TLC had associated CCLs with the majority showing flat epithelial atypia (FEA). CCL, DCIS and invasive lesions co-localized in >80% patients; LN occured in only 16% cases compared to 91% ILCs. Immunohistochemistry: Epithelial cells in the putative precursor FEA, ADH, LN, DCIS lesions and associated cancers were negative for basal/ myoepithelial markers but positive for CK19/18/8, ER-, Bcl-2, and Cyclin D-1. Contiguous cells expressing ER- increased in columnar cell hyperplasia (CCH), rising with atypia. ER-/ER-ratio and Cyclin D-1 expression increased during carcinogenesis. Bcl-2 was frequent in epithelial cells lining CCLs, ADH, LN and low grade DCIS compared to associated carcinoma. FHIT and ATM expression was reduced in hyperplastic CCLs, ADH/DCIS, LN and associated invasive lesions.
Conclusions: We suggest that CCLs, particularly FEA, are common in low grade breast carcinoma and ILC, representing a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal A subclass. Our results suggest that the committed progenitor cells for low grade breast neoplasia are CK19/18/8+, ER- and Bcl-2+. The balance between ER-/ER- expression may be important in driving cyclin D-1 and Bcl-2 expression. Alternatively, breast cancer stem/ progenitor cells regardless of their original phenotype acquire early stochastic genetic/epigenetic hits, leading to activation of the luminal A pathway (ER/cyclin D1 pathways) that determine the phenotype of pre-invasive and invasive lesions. We speculate that once cells commit to this molecular pathway, progression to a high grade (basal-like or HER2) phenotype would be unlikely.
Category: Breast

Monday, March 26, 2007 11:15 AM

Platform Session: Section D, Monday Morning