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Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors

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Abstract

Identification of novel targets for the treatment of basal-like breast cancer is essential for improved outcomes in patients with this disease. This study investigates the association of MMP7 expression and MMP7 promoter methylation with subtype and outcome in breast cancer patient cohorts. Immunohistochemical analysis was performed on a breast cancer tissue microarray and validated in independent histological samples. MMP7 expression significantly correlated with patient age, tumor size, triple-negative (TN) status, and recurrence. Analysis of publically available datasets confirmed MMP7 gene expression as a prognostic marker of breast cancer metastasis, particularly metastasis to the brain and lungs. Methylation of the MMP7 promoter was assessed by methylation-specific PCR in a panel of breast cancer cell lines and patient tumor samples. Hypomethylation of the MMP7 promoter significantly correlated with TN status in DNA from patient tumor samples, and this association was confirmed using The Cancer Genome Atlas (TCGA) dataset. Evaluation of a panel of breast cancer cell lines and data from the Curtis and TCGA breast carcinoma datasets revealed that elevated MMP7 expression and MMP7 promoter hypomethylation are specific biomarkers of the basal-like molecular subtype which shares considerable, but not complete, overlap with the clinical TN subtype. Importantly, MMP7 expression was identified as an independent predictor of pathological complete response in a large breast cancer patient cohort. Combined, these data suggest that MMP7 expression and MMP7 promoter methylation may be useful as prognostic biomarkers. Furthermore, MMP7 expression and promoter methylation analysis may be effective mechanisms to distinguish basal-like breast cancers from other triple-negative subtypes. Finally, these data implicate MMP7 as a potential therapeutic target for the treatment of basal-like breast cancers.

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Acknowledgments

This work was supported by grants from the Department of Defense W81XWH-09-1-0696 (to STS) and RO1 CA090398 and RO1 CA154384 (to RAK). The Tissue Procurement and Histology Core Facility of the Case Comprehensive Cancer Center (P30 CA043703) was instrumental in the development of the TMA. We thank Darcie Seachrist of the Department of Pharmacology at Case Western Reserve University for her assistance in acquiring images of the pathological samples. We would also like to thank Michael Goggins, M.D. of the Departments of Pathology, Oncology and Medicine at The Johns Hopkins Medical Institute for the primer sequences used to detect the MMP7 promoter methylation status.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Author notes

  1. Steven T. Sizemore

    Present address: Department of Radiation Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

  2. Gina M. Sizemore

    Present address: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA

  3. Stefanie Avril

    Present address: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106-4965, USA

    Steven T. Sizemore, Gina M. Sizemore & Ruth A. Keri

  2. Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Christine N. Booth & Fadi W. Abdul-Karim

  3. Department of Family Medicine and Community Health, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Cheryl L. Thompson

  4. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Paula Silverman

  5. Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Gurkan Bebek

  6. Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Gurkan Bebek

  7. Department of Pathology, Technical University Munich, 81675, Munich, Germany

    Stefanie Avril

  8. Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Ruth A. Keri

  9. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Ruth A. Keri

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  1. Steven T. Sizemore
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Correspondence to Ruth A. Keri.

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Sizemore, S.T., Sizemore, G.M., Booth, C.N. et al. Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors. Breast Cancer Res Treat 146, 25–40 (2014). https://doi.org/10.1007/s10549-014-2989-4

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