A DAAM1 3'-UTR Variant Promotes Breast Cancer Metastasis Via Reducing microRNA-208a-5p Binding Affinity

Background: Dishevelled-associated activator of morphogenesis 1 (DAAM1) is a commonly expressed member of diaphanous-related formins and plays a key role in controlling the migration and haptotaxis of breast cancer cells. However, the genotype and pathological type of DAAM1 in breast cancer patients remains largely unknown. Methods: We utilized a large patient cohort and breast cancer cells to determine the role of functional SNP in microRNA-208a-5p binding site of DAAM1 3'-UTR and associated mechanism in breast cancer metastasis. Findings: The expression and activation of DAAM1 increased markedly in lymphnode metastatic tissues. A genetic variant (rs79036859 A/G) was present in the miR-208a-5p binding site of DAAM1 3'-UTR. Compared with the AA genotype, G was a risk genotype for the metastasis of breast cancer by reducing binding affinity of miR-208a-5p for the DAAM1 3'-UTR. Furthermore, the miR-208a-5p expression level was significantly suppressed in lymphnode metastatic tissues. Overexpression of miR-208a-5p inhibited DAAM1/RhoA signaling pathway and thus leaded to decreasing of the migratory ability. Interpretation: We imply that the rs79036859 G variant of DAAM1 3'-UTR contributes to the likelihood of breast cancer metastasis via a novel mechanism of subtle gene regulation through miR-208a-5p binding capacity. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (81472703) to Yichao Zhu, the Natural Science Foundation of Jiangsu Province (Grant No. BK20181367) to Yichao Zhu, and the Science and Technology Foundation of Nanjing Medical University (2017NJMU001) to Ting Yan. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Ethical approval for the study was obtained from the Clinical Research Ethics Committee, Nanjing Medical University. Pathologic staging was determined by a pathologist based on AJCC Cancer Staging Manual 8th classification criteria. All the participants voluntarily joined this study with informed constents.