Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors.
Transcriptional profiling has identified five breast cancer subtypes, of which the basal epithelial is most aggressive and correlates with poor prognosis. These tumors display a high degree of cellular heterogeneity and lack established molecular targets, such as estrogen receptor-alpha, progesterone receptor, and Her2 overexpression, indicating a need for definitive diagnostic markers. We present evidence that nestin, a previously described marker of regenerative cells in diverse tissues, is expressed in the regenerative compartment of the normal human mammary gland. Colocalization studies indicate two distinct populations of mammary epithelia that express nestin: one expressing cytokeratin 14 (CK14) and DeltaN-p63 and another expressing desmin. Immunohistochemical analysis indicates that DeltaN-p63 and nestin are coordinately expressed during pregnancy in the murine mammary gland. In the embryonal carcinoma cell line NT2/D1, ectopic DeltaN-p63-alpha disrupts retinoic acid-induced differentiation, thereby preserving expression of nestin; however, small interfering RNA-mediated ablation of nestin is insufficient to promote differentiation, indicating that whereas nestin may identify cells within the regenerative compartment of the mammary gland, it is insufficient to block differentiation and preserve replicative capacity. Immunohistochemical analysis of basal epithelial breast tumors, including those shown to carry BRCA1 mutations, indicates robust expression of nestin and CK14, punctate expression of p63, and low to undetectable levels of desmin expression. Nestin was not detected in other breast cancer subtypes, indicating selectivity for basal epithelial breast tumors. These studies identify nestin as a selective marker of the basal breast cancer phenotype, which displays features of mammary progenitors.
Li
Hua
H
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Cherukuri
Pratima
P
Li
Na
N
Cowling
Victoria
V
Spinella
Michael
M
Cole
Michael
M
Godwin
Andrew K
AK
Wells
Wendy
W
DiRenzo
James
J
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018236:Carcinoma, Embryonal / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis* / Q000378:metabolism; D053547:Keratin-14 / Q000096:biosynthesis; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000378:metabolism; D064231:Nestin; D011247:Pregnancy; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000378:metabolism
D004268:DNA-Binding Proteins; D007381:Intermediate Filament Proteins; D053547:Keratin-14; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins