The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice.

BACKGROUND: Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood. METHODS: To address this, mouse models of mammary carcinogenesis were created expressing full-length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs. RESULTS: Overexpression of full-length MUC1 resulted in tumor formation in young mice (≤12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background. CONCLUSIONS: This study is the first spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation.

Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways.

Much of the ability of the MUC1 oncoprotein to foster tumorigenesis and tumor progression likely originates from the interaction of its cytoplasmic tail with proteins involved in oncogenic signaling. Many of these interactions are regulated by phosphorylation, as the cytoplasmic tail contains seven highly conserved tyrosines and several serine/threonine phosphorylation sites. We have developed a cell line-based model system to study the effects of tyrosine phosphorylation on MUC1 signaling, with particular emphasis on its effects on gene transcription. COS-7 cells, which lack endogenous MUC1, were stably infected with wild-type MUC1 or a MUC1 construct lacking all seven tyrosines (MUC1 Y0) and analyzed for effects on transcription mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappaB (NF-kappaB) pathways. COS.MUC1 Y0 cells showed heightened active ERK1/2 with increased activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) transcriptional activity; there was also a simultaneous decrease in NF-kappaB transcriptional activity and nuclear localization. These changes altered the phenotype of COS.MUC1 Y0 cells, as this line displayed increased invasion and enhanced [(3)H]thymidine incorporation. Analysis of the three lines also showed significant differences in their cell cycle profile and bromodeoxyuridine incorporation when the cells were serum starved. These data support the growing evidence that MUC1 is involved in transcriptional regulation and link MUC1 for the first time to the NF-kappaB pathway.

MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation.

MUC1 is a transmembrane mucin that was initially cloned from malignant mammary epithelial cells as a tumor antigen. More than 90% of human breast carcinomas overexpress MUC1. Numerous studies have demonstrated an interaction between MUC1 and other oncogenic proteins such as beta-catenin, erbB receptors and c-Src, but a functional role for MUC1 in transformation has not been identified. We previously reported the development of transgenic mice that overexpress human MUC1 in the mouse mammary gland (MMTV-MUC1). Analysis of these transgenic mice at an early age demonstrated the ability of MUC1 to potentiate EGF-dependent activation of MAP kinase signaling pathways in the lactating mammary gland. We now report that multiparous MMTV-MUC1 transgenic mice stochastically develop unifocal mammary gland carcinomas late in life. Molecular analysis of these tumors shows a tumor-specific coimmunoprecipitation between MUC1 and beta-catenin. Examination of the contralateral glands in MMTV-MUC1 transgenics demonstrates that the development of frank carcinomas is accompanied by a failure of multiparous glands to undergo postlactational involution. Furthermore, uniparous MMTV-MUC1 transgenic mice display decreased postlactational apoptosis, elevated whey acidic protein expression and aberrant pErk2 activation. These findings are the first to determine that MUC1 overexpression promotes in vivo transformation of the mammary gland.