Synemin (SYNM) is a type IV intermediate filament that has recently been shown to interact with the LIM domain protein zyxin, thereby possibly modulating cell adhesion and cell motility. Owing to this multiplicity of potential functions relevant to cancer development, we initiated a study to decipher SYNM expression and regulation in benign human breast tissue and breast cancer. Dot blot array analysis showed significant SYNM mRNA downregulation in 86% (n ¼ 100, Po0.001) of breast cancers compared with their normal tissue counterparts, a result that was confirmed by real-time PCR analysis (n ¼ 36, Po0.0001). Immunohistochemistry analysis showed abundant SYNM protein expression in healthy myoepithelial breast cells, whereas SYNM expression loss was evident in 57% (n ¼ 37, Po0.001) of breast cancer specimens. Next, we analyzed methylation of the SYNM promoter to clarify whether the SYNM gene can be silenced by epigenetic means. Indeed, methylation-specific PCR analysis showed tumor-specific SYNM promoter methylation in 27% (n ¼ 195) of breast cancers. As expected, SYNM promoter methylation was tightly associated (Po0.0001) with SYNM expression loss. Indepth analysis of the SYNM promoter by pyrosequencing showed extensive CpG methylation of DNA elements supposed to regulate gene transcription. Demethylating treatment of SYNM methylated breast cancer cell lines with 5-aza-2-deoxycytidine clearly reestablished the SYNM expression. Statistical analysis of the patient cohort showed a close association between SYNM promoter methylation and unfavorable recurrence-free survival (hazard ratio ¼ 2.941, P ¼ 0.0282). Furthermore, SYNM methylation positively correlated with lymph node metastases (P ¼ 0.0177) and advanced tumor grade (P ¼ 0.0275), suggesting that SYNM methylation is associated with aggressive forms of breast cancer. This is the first study on the epigenetic regulation of the SYNM gene in a cancer entity. We provide first hints that SYNM could represent a novel putative breast tumor suppressor gene that is prone to epigenetic silencing. SYNM promoter methylation may become a useful predictive biomarker to stratify breast cancer patients' risk for tumor relapse.

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Further studies and validations are required; in the tumors of patients with PDAC without activating mutations and induced expression of EGFR/KRAS genes, down-regulated miR-216b expression may be associated with a poor response to radiotherapy via deregulation of another signaling pathway related to FGFR1 signaling.

The Homeobox B13 (HOXB13):Interleukin 17 Receptor B (IL17BR) index of estrogen receptor (ER)-positive breast cancer (ER (+) BC) patients may be a potential biomarker of recurrence/ metastasis. However, effects of microRNA (miRNA) binding to the 3' untranslated region (3´UTR) of HOXB13 and IL17BR and its function on recurrence/metastasis in ER (+) BC remains elusive. The aims of this study were to determine the expression of miRNAs that bind to 3´UTR of HOXB13 and IL17BR in ER (+) BC patients and asess the effects of these miRNAs on recurrence/metastasis. The expression profiles of HOXB13 and IL17BR were evaluated using RT-PCR in tumors and normal tissue samples from 40 ER (+) BC patients. The expression level of 4 miRNAs, which were predicted to bind the 3´UTR of HOXB13 and IL17BR using TargetScan, microRNA.org and miRDB online databases, were further evaluated with RT-PCR. Our findings demonstrated that high miR-1266 levels might be significant prognostic factor for recurrence/metastasis occurrence (3.05 fold p=0.004) and tamoxifen response (3.90 fold; p=0.2514) in ER (+) BC cases. Although we suggest that modulation of miR-1266 expression may be an important mechanism underlying the chemoresistance of ER (+) BC, advanced studies and validation are required.

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