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

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.

Genome-wide DNA methylation patterns of bovine blastocysts derived from in vivo embryos subjected to in vitro culture before, during or after embryonic genome activation

“…Conceptually, for genes to be expressed, the DNA sequence must be accessible for the transcriptional machinery and any blockage of the transcription machinery could potentially shutdown the gene expression [ 41 ]. Among these, hypomethylation (removal of the DNA methylation marks) around the promoter region is believed to increase the transcriptional activity of the genes [ 42 – 44 ]. During normal embryo development, the fertilized egg undergoes multiple epigenetic modifications, which subsequently affect the resulting gene expression profiles.…”

MMP7 interacts with ARF in nucleus to potentiate tumor microenvironments for prostate cancer progression in vivo

“…Nuclear MMP3 activates CCN2 gene transcription for IL-6-mediated cell migration [28, 32]. As MMP7 is associated with the malignant features of cancers [33, 34], our findings offer novel and valuable insights into understanding the functions of MMP7 in PCa as following: 1) MMP7 shuttles to nucleus without being cleaved, and it certainly deserves further investigation to elucidate the mechanisms on shuttling and the biological actions of MMP7 in nucleus of PCa cells; 2) ARF binds pro-MMP7 (~30 kDa) not active-MMP7 (~19 kDa) in nucleus, and it will be interesting to know these binding domains of MMP7 and ARF proteins; 3) Nuclear factors associated with ARF-MMP7 in nuclear compartments promote cell migration of PCa cells. ARF knockdown decreases MMP7 at both the transcription and the protein stability (Supplementary Figures S3 and S4), suggesting the ARF-MMP7 binding in nucleus may prevent pro-MMP7 from degradation.…”

Identification of Biomarkers for Breast Cancer Using Databases

“…Through TCGA data and patients in the Breast Cancer Care in Chicago, high levels of promoter methylation were found to be strongly associated with hormone-receptor-positive status of breast tumors 12. Matrix metalloproteinase (MMP)-7 expression is related with methylation and it was confirmed from TCGA that hypomethylation of MMP-7 promoter is a prognosis marker 13. Methylation state of DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES genes may be correlated with worse breast cancer survival in African American 14…”