MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation

Abstract

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 b-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 b-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.

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

“…It was interesting to see that, to the exception of PLU-1/JARID1B (Lu et al, 1999), all the genes identified in our study were newly proposed as candidate cancer genes. Furthermore, MUC1 (Schroeder et al, 2004), a long known cell surface marker overexpressed in a sizeable fraction of breast tumours, and KIF14 (Corson et al, 2005), a recently proposed candidate at 1q31, presented DSs below the threshold and were excluded from our selection. Genes selected in our study belong to rather diverse functional groups, of which three appeared prevalent.…”

Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis

“…Activation of MAPK in association with MUC1 has been demonstrated in vitro and in the mammary glands of MMTV-MUC1 transgenic mice (Meerzaman et al, 2001;Schroeder et al, 2001). In addition, mammary gland tumors induced by overexpression of MUC1 showed increased Erk activation, and involuting MMTV-MUC1 mammary glands expressed higher levels of activated Erk2 (Schroeder et al, 2004). Erk2 has been reported to play a critical role in mediating proliferation in breast cancer cells (Flury et al, 1997).…”

“…Thoracic mammary glands were prepared for protein analysis as previously described (Schroeder et al, 2004).…”

“…Lack of Muc1 expression leads to a significant delay in tumor onset in the mouse mammary tumor virus (MMTV)-Wnt-1 mouse model of breast cancer, suggesting that Muc1 is involved in the initiation stages of cancer in that b-catenin-dependent model (Schroeder et al, 2003). We have recently shown that MUC1 overexpression promotes in vivo transformation of the mammary gland, establishing that MUC1 is not merely a by-product of transformation but can itself promote transformation in a physiological context (Schroeder et al, 2004). To elucidate the role of MUC1 in tumor progression and metastasis, we crossed MMTV-driven polyoma middle T-antigen (MMTVPyV MT) transgenic mice onto a Muc1 null background (Spicer et al, 1995b).…”

MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90

“…Other studies have shown that MUC1 also binds directly to p53 and regulates transcription of p53-target genes (Wei et al, 2005). Notably, overexpression of MUC1 is sufficient to induce anchorage-independent growth and tumorigenicity (Ren et al, 2002;Huang et al, 2003;Li et al, 2003b;Schroeder et al, 2004).…”