Methylation signature of lymph node metastases in breast cancer patients

Abstract

BackgroundInvasion and metastasis are two important hallmarks of malignant tumors caused by complex genetic and epigenetic alterations. The present study investigated the contribution of aberrant methylation profiles of cancer related genes, APC, BIN1, BMP6, BRCA1, CST6, ESR-b, GSTP1, P14 (ARF), P16 (CDKN2A), P21 (CDKN1A), PTEN, and TIMP3, in the matched axillary lymph node metastasis in comparison to the primary tumor tissue and the adjacent normal tissue from the same breast cancer patients to identify the potential of candidate genes methylation as metastatic markers.MethodsThe quantitative methylation analysis was performed using the SEQUENOM’s EpiTYPER™ assay which relies on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).ResultsThe quantitative DNA methylation analysis of the candidate genes showed higher methylation proportion in the primary tumor tissue than that of the matched normal tissue and the differences were significant for the APC, BIN1, BMP6, BRCA1, CST6, ESR-b, P16, PTEN and TIMP3 promoter regions (P<0.05). Among those candidate methylated genes, APC, BMP6, BRCA1 and P16 displayed higher methylation proportion in the matched lymph node metastasis than that found in the normal tissue (P<0.05). The pathway analysis revealed that BMP6, BRCA1 and P16 have a role in prevention of neoplasm metastasis.ConclusionsThe results of the present study showed methylation heterogeneity between primary tumors and metastatic lesion. The contribution of aberrant methylation alterations of BMP6, BRCA1 and P16 genes in lymph node metastasis might provide a further clue to establish useful biomarkers for screening metastasis.

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

“…BMP6 expression in ER-negative breast cancer was obviously lower than that in ER-positive breast cancer. Previous studies have shown that promoter hypermethylation contributes to the downregulation of BMP6 expression in ER-negative breast cancer patients (15,16). Our results were in agreement with a previous observation (7) and moreover, further analysis also revealed a significant association between tumor cell grade and BMP6 expression in tumor tissues.…”

CXCL12 and ADAM23 hypermethylation are associated with advanced breast cancers

“…In recent studies, the simultaneous presence of RASSF1A and APC methylation from PTs to LNMs was detected. 36,51 In 57 patients, we observed very similar DNA methylation levels in all 4 hypermethylated genes (RASSF1A, APC, CXCL12, and ADAM23) in both the LNM and PT tissues. Taking into account the tumor heterogeneity, we hypothesize that there are partially degraded cell populations present in the circulation, originating from detached cancer cells that are not able to survive and form metastases but have different methylation profiles; their fragments could be represented by a portion of cfDNA in the PL.…”

Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells

“…These indicated that hypermethylation of BMP6 promoter might be involved in breast tumorigenesis and drug resistance. In fact, previous studies also confirmed that aberrant methylation of BMP6 is involved in various cancers including malignant lymphoma, malignant pleural mesothelioma, T-cell leukemia and multiple myeloma (20,21,(25)(26)(27). In the present study, we noted that aberrant methylation of BMP6 promoter was involved in breast cancer cell drug resistance.…”