Breast Cancer Research and Treatment

, Volume 146, Issue 1, pp 25–40

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

  • Steven T. Sizemore
  • Gina M. Sizemore
  • Christine N. Booth
  • Cheryl L. Thompson
  • Paula Silverman
  • Gurkan Bebek
  • Fadi W. Abdul-Karim
  • Stefanie Avril
  • Ruth A. Keri
Preclinical study

DOI: 10.1007/s10549-014-2989-4

Cite this article as:
Sizemore, S.T., Sizemore, G.M., Booth, C.N. et al. Breast Cancer Res Treat (2014) 146: 25. doi:10.1007/s10549-014-2989-4

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.

Keywords

MMP7Triple negativeBasal-likeBreast cancerMetastasisPromoter methylation

Supplementary material

10549_2014_2989_MOESM1_ESM.pptx (9.7 mb)
Supplementary material 1 (PPTX 9957 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Steven T. Sizemore
    • 1
    • 10
  • Gina M. Sizemore
    • 1
    • 11
  • Christine N. Booth
    • 2
  • Cheryl L. Thompson
    • 3
  • Paula Silverman
    • 4
  • Gurkan Bebek
    • 5
    • 6
  • Fadi W. Abdul-Karim
    • 2
  • Stefanie Avril
    • 7
    • 12
  • Ruth A. Keri
    • 1
    • 8
    • 9
  1. 1.Department of PharmacologyCase Western Reserve University School of MedicineClevelandUSA
  2. 2.Department of Anatomic PathologyCleveland Clinic FoundationClevelandUSA
  3. 3.Department of Family Medicine and Community HealthCase Western Reserve University School of MedicineClevelandUSA
  4. 4.Department of MedicineCase Western Reserve University School of MedicineClevelandUSA
  5. 5.Center for Proteomics and BioinformaticsCase Western Reserve University School of MedicineClevelandUSA
  6. 6.Genomic Medicine InstituteCleveland Clinic FoundationClevelandUSA
  7. 7.Department of PathologyTechnical University MunichMunichGermany
  8. 8.Division of General Medical Sciences-OncologyCase Western Reserve University School of MedicineClevelandUSA
  9. 9.Department of GeneticsCase Western Reserve University School of MedicineClevelandUSA
  10. 10.Department of Radiation OncologyComprehensive Cancer Center, The Ohio State UniversityColumbusUSA
  11. 11.Department of Molecular and Cellular Biochemistry, College of MedicineThe Ohio State UniversityColumbusUSA
  12. 12.Department of PathologyCase Western Reserve University School of MedicineClevelandUSA