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Mucin 2 (MUC2) modulates the aggressiveness of breast cancer

  • Preclinical study
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Abstract

Purpose

Tumors that secrete large volumes of mucus are chemotherapy resistant, however, mechanisms underlying this resistance are unknown. One protein highly expressed in mucin secreting breast cancers is the secreted mucin, Mucin 2 (MUC2). While MUC2 is expressed in some breast cancers it is absent in normal breast tissue, implicating it in breast cancer. However, the effects of MUC2 on breast cancer are largely unknown. This study examined the role of MUC2 in modulating breast cancer proliferation, response to chemotherapy and metastasis.

Methods

Using patient derived xenografts we developed two novel cell lines, called BCK4 and PT12, which express high levels of MUC2. To modulate MUC2 levels, BCK4 and PT12 cells were engineered to express shRNA targeted to MUC2 (shMUC2, low MUC2) or a non-targeting control (shCONT, high MUC2) and proliferation and apoptosis were measured in vitro and in vivo. BCK4 cells with shCONT or shMUC2 were labeled with GFP-luciferase and examined in an experimental metastasis model; disease burden and site specific dissemination were monitored by intravital imaging and fluorescence guided dissection, respectively.

Results

Proliferation decreased in BCK4 and PT12 shMUC2 cells versus control cells both in vitro and in vivo. Chemotherapy induced minimal apoptosis in control cells expressing high MUC2 but increased apoptosis in shMUC2 cells containing low MUC2. An experimental metastasis model showed disease burden decreased when breast cancer cells contained low versus high MUC2. Treatment with Epidermal Growth Factor (EGF) increased MUC2 expression in BCK4 cells; this induction was abolished by the EGF-receptor inhibitor, Erlotinib.

Conclusions

MUC2 plays an important role in mediating proliferation, apoptosis and metastasis of breast cancer cells. MUC2 may be important in guiding treatment and predicting outcomes in breast cancer patients.

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Data availability

Data generated during this study are included in this published article and its supplementary information files, available online.

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Acknowledgements

We thank Dr. Carol Sartorius for helpful comments on the manuscript. We also thank the following University of Colorado Cancer Center Core laboratories: Tissue Culture Core, Functional Genomics Facility, the University of Colorado Cancer Center (P30CA046984), and the University of Colorado Anschutz Medical Campus Biorepository Core Facility.

Funding

This study was supported by the University of Colorado Cancer Center Core Laboratories (P30CA046984). Funding provided by the University of Colorado Department of Pathology and the Breast Cancer Research Foundation. Studies also supported (in part) by a research grant from the Cancer League of Colorado, Inc (to BMJ).

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Authors and Affiliations

  1. Department of Pathology, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8104, Aurora, CO, 80045, USA

    Anna Astashchanka, Thomas M. Shroka & Britta M. Jacobsen

  2. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, Mail Stop 8104, Aurora, CO, 80045, USA

    Britta M. Jacobsen

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  1. Anna Astashchanka
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Correspondence to Britta M. Jacobsen.

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Anna Astashchanka declares that she has no conflict of interest. Thomas M. Shroka declares that he has no conflict of interest. Britta M. Jacobsen declares that she has no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Astashchanka, A., Shroka, T.M. & Jacobsen, B.M. Mucin 2 (MUC2) modulates the aggressiveness of breast cancer. Breast Cancer Res Treat 173, 289–299 (2019). https://doi.org/10.1007/s10549-018-4989-2

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