title: A novel miR-34a target, protein kinase D1, stimulates cancer stemness and drug resistance through GSK3/β-catenin signaling in breast cancer.
abstract: One of the properties of human breast cancer cells is cancer stemness, which is characterized by self-renewal capability and drug resistance. Protein kinase D1 (PRKD1) functions as a key regulator of many cellular processes and is downregulated in invasive breast cancer cells. In this study, we found that PRKD1 was upregulated in MCF-7-ADR human breast cancer cells characterized by drug resistance. Additionally, we discovered that PRKD1 expression was negatively regulated by miR-34a binding to the PRKD1 3'-UTR. PRKD1 expression increased following performance of a tumorsphere formation assay in MCF-7-ADR cells. We also found that reduction of PRKD1 by ectopic miR-34a expression or PRKD1 siRNA treatment resulted in suppressed self-renewal ability in breast cancer stem cells. Furthermore, we confirmed that the PRKD1 inhibitor CRT0066101 reduced phosphorylated PKD/PKCμ, leading to suppression of breast cancer stemness through GSK3/β-catenin signaling. PRKD1 inhibition also influenced apoptosis initiation in MCF-7-ADR cells. Tumors from nude mice treated with miR-34a or CRT0066101 showed suppressed tumor growth, proliferation, and induced apoptosis. These results provide evidence that regulation of PRKD1, a novel miR-34a target, contributes to overcoming cancer stemness and drug resistance in human breast cancer.
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Do Yeon
authors.initials: do Y
authors.lastname: Kim
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: EunSun
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyeok-Gu
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Koo
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Je Yeong
authors.initials: JY
authors.lastname: Ko
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kong
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D051176:beta Catenin; D004317:Doxorubicin; C089212:protein kinase D; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3
keywords: PRKD1; cancer stemness; drug resistance; miR-34a; β-catenin signaling