title: Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family.
abstract: We have previously provided evidence showing an association between some precursor lesions with low nuclear grade breast carcinomas (LNGBCs). In this study, further immunophenotypic support to our proposed route of pathogenesis of LNGBC and their precursor lesions was provided. Precursor lesions including columnar cell lesions, atypical ductal hyperplasia, ductal carcinoma in situ, usual epithelial hyperplasia, and lobular neoplasia were compared with matching "morphologically normal" terminal lobular duct units and matching invasive carcinoma. The epithelial cells in the putative precursor flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia, ductal carcinoma in situ lesions, and their coexisting LNGBC were negative for basal and myoepithelial markers, but positive for CK19/18/8, estrogen receptor (ER)-alpha, Bcl-2, and cyclin D1. The ER-alpha/ER-beta expression ratio increased during carcinogenesis, as did expression of cyclin D1 and Bcl-2. p53 immunopositivity was found 3% in LNGBC versus 43% in high nuclear grade breast carcinoma (HNGBC), whereas ataxia telangiectasia mutated expression was absent or reduced in 22% of LNGBC versus 53% of HNGBC cases. In summary, our findings support the concept that flat epithelial atypia is the earliest morphologically identifiable nonobligate precursor lesion of LNGBC. These may represent a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal "A" subclass of breast cancer. The balance between ER-alpha and ER-beta expression may be important in driving cyclin D-1 and Bcl-2 expression. Ataxia telangiectasia mutated may be one of the alternative regulatory mechanisms to TP53 mutation or dysfunction in low-grade and high-grade breast carcinoma. Our findings support the concept that progression of LNGBC to HNGBC (basal-like or HER2+) phenotype is an unlikely biologic phenomenon.
authors.affiliation: Division of Pathology, School of Molecular Medical Sciences and Nottingham University Hospitals Trust, University of Nottingham, Nottingham, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.forename: Desmond G
authors.initials: DG
authors.lastname: Powe
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Hodi
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Andrew H S
authors.initials: AH
authors.lastname: Lee
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D047628:Estrogen Receptor alpha / Q000032:analysis; D047629:Estrogen Receptor beta / Q000032:analysis; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000032:analysis; D053539:Keratin-19 / Q000032:analysis; D053533:Keratin-8 / Q000032:analysis; D042361:Mammary Glands, Human / Q000737:chemistry* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D011230:Precancerous Conditions / Q000737:chemistry* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C488421:KRT18 protein, human; C426203:KRT8 protein, human; D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases