PMID- 30100605 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2157-9024 (Print) IS - 2157-9024 (Electronic) IS - 2157-9024 (Linking) VI - 7 IP - 8 DP - 2018 Aug 13 TI - Notch3 inhibits epithelial-mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. PG - 59 LID - 10.1038/s41389-018-0069-z [doi] LID - 59 AB - Notch3 and GATA binding protein 3 (GATA-3) have been, individually, shown to maintain luminal phenotype and inhibit epithelial-mesenchymal transition (EMT) in breast cancers. In the present study, we report that Notch3 expression positively correlates with that of GATA-3, and both are associated with estrogen receptor-alpha (ERalpha) expression in breast cancer cells. We demonstrate in vitro and in vivo that Notch3 suppressed EMT and breast cancer metastasis by activating GATA-3 transcription. Furthermore, Notch3 knockdown downregulated GATA-3 and promoted EMT; while overexpression of Notch3 intracellular domain upregulated GATA-3 and inhibited EMT, leading to a suppression of metastasis in vivo. Moreover, inhibition or overexpression of GATA-3 partially reversed EMT or mesenchymal-epithelial transition induced by Notch3 alterations. In breast cancer patients, high GATA-3 expression is associated with higher Notch3 expression and lower lymph node metastasis, especially for hormone receptor (HR) positive cancers. Herein, we demonstrate a novel mechanism whereby Notch3 inhibit EMT by transcriptionally upregulating GATA-3 expression, at least in part, leading to the suppression of cancer metastasis in breast cancers. Our findings expand our current knowledge on Notch3 and GATA-3's roles in breast cancer metastasis. FAU - Lin, Hao-Yu AU - Lin HY AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - Department of Breast and Thyroid Surgery, The First Affiliated Hospital of SUMC, Shantou, China. FAU - Liang, Yuan-Ke AU - Liang YK AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. FAU - Dou, Xiao-Wei AU - Dou XW AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Chen, Chun-Fa AU - Chen CF AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - Department of Breast and Thyroid Surgery, The First Affiliated Hospital of SUMC, Shantou, China. FAU - Wei, Xiao-Long AU - Wei XL AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - Department of Pathology, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Zeng, De AU - Zeng D AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - Department of Breast Medical Oncology, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Bai, Jing-Wen AU - Bai JW AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - The Cancer Center, Xiang'an Hospital, Xiamen University Medical College, Xiang'an Dong Rd, 2000, Xiamen, China. FAU - Guo, Yu-Xian AU - Guo YX AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Lin, Fang-Fang AU - Lin FF AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Huang, Wen-He AU - Huang WH AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Du, Cai-Wen AU - Du CW AD - Department of Oncology, Shenzhen Hospital of Chinese Academy of Medical Science affiliated Cancer Hospital, Shenzhen, China. FAU - Li, Yao-Chen AU - Li YC AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. FAU - Chen, Min AU - Chen M AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. mchenst@outlook.com. FAU - Zhang, Guo-Jun AU - Zhang GJ AUID- ORCID: 0000-0001-5182-5887 AD - The Breast Center, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. guoj_zhang@yahoo.com. AD - ChangJiang Scholar's Laboratory, The Cancer Hospital of Shantou University Medical College (SUMC), Shantou, China. guoj_zhang@yahoo.com. AD - The Cancer Center, Xiang'an Hospital, Xiamen University Medical College, Xiang'an Dong Rd, 2000, Xiamen, China. guoj_zhang@yahoo.com. LA - eng PT - Journal Article DEP - 20180813 PL - United States TA - Oncogenesis JT - Oncogenesis JID - 101580004 PMC - PMC6087713 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/08/14 06:00 MHDA- 2018/08/14 06:01 PMCR- 2018/08/13 CRDT- 2018/08/14 06:00 PHST- 2017/11/21 00:00 [received] PHST- 2018/06/11 00:00 [accepted] PHST- 2018/06/06 00:00 [revised] PHST- 2018/08/14 06:00 [entrez] PHST- 2018/08/14 06:00 [pubmed] PHST- 2018/08/14 06:01 [medline] PHST- 2018/08/13 00:00 [pmc-release] AID - 10.1038/s41389-018-0069-z [pii] AID - 69 [pii] AID - 10.1038/s41389-018-0069-z [doi] PST - epublish SO - Oncogenesis. 2018 Aug 13;7(8):59. doi: 10.1038/s41389-018-0069-z.