Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival

Mariya Farooqui, Laura R. Bohrer, Nicholas J. Brady, Pavlina Chuntova, Sarah E. Kemp, C. Taylor Wardwell, Andrew C. Nelson, Kathryn L. Schwertfeger

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background: The epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis. Methods: EREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo. Results: In comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples. Conclusions: Together, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.

Original languageEnglish (US)
Article number138
JournalMolecular Cancer
Issue number1
StatePublished - Jul 29 2015

Bibliographical note

Funding Information:
The authors would like to thank Dr. Cheuk Leung (University of Minnesota) for input on three-dimensional cell culture models, Dr. Fariba Behbod (University of Kansas Medical Center) for providing cells and input on these studies, Dr. Joseph Koopmeiners for input with statistical analysis and Adrian Chang for technical assistance. We would like to acknowledge the use of the confocal microscope at the Masonic Cancer Center made available through an NCRR Shared Instrumentation Grant (#1 S10 RR16851). Funding provided by NIH/NCI R01CA132827, American Cancer Society RSG-09-192-01-LIB and the Prospect Creek Foundation to K.L.S.

Publisher Copyright:
© 2015 Farooqui et al.


  • Breast cancer
  • Ductal carcinoma in situ
  • Epiregulin
  • FGFR
  • MMP-1


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