title: Active signaling by HER-2/neu in a subpopulation of HER-2/neu-overexpressing ductal carcinoma in situ: clinicopathological correlates.
abstract: HER-2/neu overexpression occurs in a proportion of invasive breast carcinomasand is an adverse prognostic indicator, although its apparent strength as a prognostic indicator varies in different studies. Paradoxically, HER-2/neu is overexpressed with particularly high frequency in ductal carcinoma in situ (DCIS). We have hypothesized and presented supporting data that HER-2/neu is actively signaling in a subset of the tumors in which it is overexpressed. We use an activation state-dependent anti-HER-2/neu monoclonal antibody (PN2A) produced in our laboratory to study this paradigm immunohistochemically. In this report, we analyze the characteristics of 219 cases of DCIS with respect to HER-2/neu expression and activation state. We find that 58% of cases of DCIS with overexpression have the receptor in the activated state, a substantially greater proportion than we have previously noted for invasive carcinomas. Although HER-2/neu overexpression in general was inversely correlated with hormone receptor expression, cases with activated HER-2/neu had the lowest hormone receptor positivity rate. Statistically significant correlations with activated HER-2/neu were not noted for tumor size, presence of calcifications, necrosis or fibrosis, or indicators of angiogenesis. These results suggest that examination of activated HER-2/neu status may better reflect the biology of a tumor than overall determination of HER-2/neu levels. Our finding that active signaling by HER-2/neu, as detected by this assay, is more frequent in DCIS than previously noted for invasive carcinoma implicates signaling by HER-2/neu as having a critical role in the early stages of breast tumorigenesis.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: DiGiovanna
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Davison
authors.forename: Christine L
authors.initials: CL
authors.lastname: Howe
authors.forename: Darryl
authors.initials: D
authors.lastname: Carter
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Claus
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone