| First Author | Khalil S | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 3 | Pages | e33421 |
| PubMed ID | 22457761 | Mgi Jnum | J:187135 |
| Mgi Id | MGI:5435390 | Doi | 10.1371/journal.pone.0033421 |
| Citation | Khalil S, et al. (2012) Activation status of Wnt/ss-catenin signaling in normal and neoplastic breast tissues: relationship to HER2/neu expression in human and mouse. PLoS One 7(3):e33421 |
| abstractText | Wnt/ss-catenin signaling is strongly implicated in neoplasia, but the role of this pathway in human breast cancer has been controversial. Here, we examined Wnt/ss-catenin pathway activation as a function of breast cancer progression, and tested for a relationship with HER2/neu expression, using a human tissue microarray comprising benign breast tissues, ductal carcinoma in situ (DCIS), and invasive carcinomas. Cores were scored for membranous ss-catenin, a key functional component of adherens junctions, and for nucleocytoplasmic ss-catenin, a hallmark of Wnt/ss-catenin pathway activation. Only 82% of benign samples exhibited membrane-associated ss-catenin, indicating a finite frequency of false-negative staining. The frequency of membrane positivity was similar in DCIS samples, but was significantly reduced in carcinomas (45%, P<0.001), consistent with loss of adherens junctions during acquisition of invasiveness. Negative membrane status in cancers correlated with higher grade (P = 0.04) and estrogen receptor-negative status (P = 0.03), both indices of poor prognosis. Unexpectedly, a substantial frequency of nucleocytoplasmic ss-catenin was observed in benign breast tissues (36%), similar to that in carcinomas (35%). Positive-staining basal nuclei observed in benign breast may identify putative stem cells. An increased frequency of nucleocytoplasmic ss-catenin was observed in DCIS tumors (56%), suggesting that pathway activation may be an early event in human breast neoplasia. A correlation was observed between HER2/neu expression and nucleocytoplasmic ss-catenin in node-positive carcinomas (P = 0.02). Furthermore, cytoplasmic ss-catenin was detected in HER2/neu-induced mouse mammary tumors. The Axin2(NLSlacZ) mouse strain, a previously validated reporter of mammary Wnt/ss-catenin signaling, was utilized to define in vivo transcriptional consequences of HER2/neu-induced ss-catenin accumulation. Discrete hyperplastic foci observed in mammary glands from bigenic MMTV/neu, Axin2(NLSlacZ) mice, highlighted by robust ss-catenin/TCF signaling, likely represent the earliest stage of mammary intraepithelial neoplasia in MMTV/neu mice. Our study thus provides provocative evidence for Wnt/ss-catenin signaling as an early, HER2/neu-inducible event in breast neoplasia. |
