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MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation

Oncogene volume 23, pages 5739–5747 (2004)Cite this article

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 β-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 β-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.

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Acknowledgements

We are grateful to Dr J Taylor-Papadimitriou for the HMFG-2 antibody and Biomira Inc. for the B27.29 antibody. We thank Dr Robert Cardiff and Dr Thomas Lidner for pathological analysis. We also thank Suresh Savarirayan and the animal care attendants for excellent animal care, Marvin H Ruona for computer graphics and Carol Williams for assistance with manuscript. This work was supported by NIH RO1CA64389 (SJG), NIH F32CA81703 (JAS), DOD Breast Cancer Research Program DAMD17-02-1-0476 (AAM) and Mayo Clinic College of Medicine.

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Author notes

  1. Joyce A Schroeder

    Present address: Department of Molecular and Cellular Biology, University of Arizona, Arizona Cancer Center, Tucson, AZ 85724, USA

  2. Melissa C Adriance

    Present address: Lawrence Berkeley National Lab, Cell and Molecular Biology, 1 Cyclotron Road, MS 83-101, Berkeley, CA 94720, USA

  3. Joyce A Schroeder and Azzah Al Masri: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Scottsdale, Scottsdale, 85259, AZ, USA

    Joyce A Schroeder, Azzah Al Masri, Jennifer C Tessier, Kari L Kotlarczyk, Melissa C Thompson & Sandra J Gendler

  2. Tumor Biology Program, Mayo Clinic College of Medicine, Mayo Clinic Scottsdale, Scottsdale, 85259, AZ, USA

    Melissa C Adriance & Sandra J Gendler

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  1. Joyce A Schroeder
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Correspondence to Sandra J Gendler.

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Schroeder, J., Masri, A., Adriance, M. et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene 23, 5739–5747 (2004). https://doi.org/10.1038/sj.onc.1207713

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