title: Id4 protein is highly expressed in triple-negative breast carcinomas: possible implications for BRCA1 downregulation.
abstract: BRCA1 germline mutation carriers usually develop ER, PR and HER2 negative breast carcinoma. Somatic BRCA1 mutations are rare in sporadic breast cancers, but other mechanisms could impair BRCA1 functions in these tumors, particularly in triple-negative breast carcinomas (TNBCs). Id4, a helix-loop-helix DNA binding factor, blocks BRCA1 gene transcription in vitro and could downregulate BRCA1 in vivo. We compared Id4 immunoreactivity in 101 TNBCs versus 113 non-TNBCs, and correlated the results with tumor morphology and immunoreactivity for CK5/6, CK14, EGFR, and androgen receptor (AR). Id4 was present in 76 out of 101 (75 %) TNBCs: 40 (40 %) TNBCs displayed Id4 positivity in >50 % of neoplastic cells, 23 (23 %) in 5-50 %, and 13 (13 %) in <5 %. In contrast, only 6 (5 %) of 113 non-TNBCs showed focal Id4 positivity, limited to fewer than 5 % of the tumor (p < 0.0001). Id4 expression significantly associated with high histologic grade (p = 0.0002) and mitotic rate (p = 0.006). Id4 decorated all 12 TNBCs with large central acellular zone of necrosis in our series, with positive staining in 10-90 % of the cells. Id4 signal strongly correlated with cytokeratin CK14 reactivity (p < 0.0001), but not with CK5/6 and EGFR. All apocrine carcinomas in our series were positive for AR and most for EGFR, but they were negative for CK5/6, CK14, and Id4, with only two exceptions. Our results document substantial expression of Id4 in most TNBCs, which could result in functional downregulation of BRCA1 pathways in these tumors.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. weny@mskcc.org
authors.forename: Yong Hannah
authors.initials: YH
authors.lastname: Wen
authors.forename: Alice
authors.initials: A
authors.lastname: Ho
authors.forename: Sujata
authors.initials: S
authors.lastname: Patil
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Akram
authors.forename: Jeff
authors.initials: J
authors.lastname: Catalano
authors.forename: Anne
authors.initials: A
authors.lastname: Eaton
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D053547:Keratin-14 / Q000276:immunology / Q000378:metabolism; D053555:Keratin-5 / Q000276:immunology / Q000378:metabolism; D053553:Keratin-6 / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011944:Receptors, Androgen / Q000276:immunology / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D051796:Inhibitor of Differentiation Proteins; D053547:Keratin-14; D053555:Keratin-5; D053553:Keratin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C492913:BRCA1 protein, human; C490128:ID4 protein, human