Methylation profile of triple-negative breast carcinomas

Branham, Marı́a Teresita; Marzese, Diego M.; Laurito, Sergio; Gago, Francisco E.; Orozco, Javier I. J.; Tello, Olga; Vargas–Roig, Laura M.; Roqué, María

doi:10.1038/oncsis.2012.17

Cited by 49 publications

(37 citation statements)

References 22 publications

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“…DNA was isolated using CTAB (Cetyltrimethyl Ammonium Bromide) as previously described [14, 15]. Classification of BRCAness phenotype was performed using the MLPA assay, probemix P376-B2 BRCA1ness according to manufacturer’s recommendations (MRC-Holland, Amsterdam, the Netherlands) [16].…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer

Branham

Campoy

Laurito

et al. 2015

Breast Cancer Res Treat

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BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinicopathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorfism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors.

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Section: Methodsmentioning

confidence: 99%

“…A CpG site was considered to be methylated when the methylation dosage ratio between digested and undigested sample was superior to the cut-off threshold of 8 %. [14, 15, 21]. Afterward, DNA methylation data were dichotomized in un methylated and methylated status.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer

Branham

Campoy

Laurito

et al. 2015

Breast Cancer Res Treat

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“…ID4 expression is also absent in ERα positive atypical ductal hyperplasia, ductal carcinoma in situ and invasive carcinomas but present in normal ER a negative mammary epithelial cells [40] suggesting that ER a could negatively regulate ID4 [39, 40]. Increased ID4 expression is observed in basal celllike breast cancer [41], triple negative breast cancer (TNBC) (including 4T1 mouse mammary cancer cell line [42, 43]) but not in non-TNBC. In meta-analysis, no significant association was found between ID4 and breast cancer [44].…”

Section: Id4 and Cancermentioning

confidence: 99%

Inhibitor of differentiation 4 (ID4): From development to cancer

Patel

Morton

Carey

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Highly conserved Inhibitor of DNA Binding (ID1-4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, 2 and 3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, 2 and 3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, 2 and 3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promotes stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.

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“…Branham et al analyzed methylation of CpG islands in 69 cancer-related genes in TNBC tumors and compared the methylation profile with non-TNBC tumors [48]. The assay used for characterization of the methylation profile was Methyl-specific multiplex ligation-dependent probe amplification assay (MS-MLPA) obtained from MRC-Holland, Amsterdam, The Netherlands (www.mrc-holland.com).…”

Section: (I) Introductionmentioning

confidence: 99%

“…The normalized peaks from the analyzed samples were compared with the normalized peaks from the control reaction. Through this method, a specific panel of genes including CDKN2B, CD44, MGMT, RB and p73 was found to be methylated in TNBC tumors, but not in non-TNBC tumors [48]. …”

Section: (I) Introductionmentioning

confidence: 99%

Epigenetics in Breast and Prostate Cancer

Sarkissyan

Vadgama

2014

Methods in Molecular Biology

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SUMMARY Most recent investigations into cancer etiology have identified a key role played by epigenetics. Specifically, aberrant DNA and histone modifications which silence tumor suppressor genes or promote oncogenes have been demonstrated in multiple cancer models. While the role of epigenetics in several solid tumor cancers such as colorectal cancer are well established, there is emerging evidence that epigenetics also plays a critical role in breast and prostate cancer. In breast cancer, DNA methylation profiles have been linked to hormone receptor status and tumor progression. Similarly in prostate cancer, epigenetic patterns have been associated with androgen receptor status and response to therapy. The regulation of key receptor pathways and activities which affect clinical therapy treatment options by epigenetics renders this field high priority for elucidating mechanisms and potential targets. A new set of methylation arrays are now available to screen epigenetic changes and provide the cuttingedge tools needed to perform such investigations. The role of nutritional interventions affecting epigenetic changes particularly holds promise. Ultimately, determining the causes and outcomes from epigenetic changes will inform translational applications for utilization as biomarkers for risk and prognosis as well as candidates for therapy.

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Methylation profile of triple-negative breast carcinomas

Cited by 49 publications

References 22 publications

Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer

Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer

Inhibitor of differentiation 4 (ID4): From development to cancer

Epigenetics in Breast and Prostate Cancer

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