title: POMC maintains tumor-initiating properties of tumor tissue-derived long-term-cultured breast cancer stem cells.
abstract: The identification and understanding of the molecular network of cancer stem cells (CSCs) have had a profound impact on our view of carcinogenesis and treatment strategy. Unfortunately, a major problem is that serial passages of CSCs from clinical solid tumor specimens currently are not available in any lab, and thus, reported data are difficult to confirm and intensively interrogated. Here, we have generated two tumor tissue-derived breast CSC (BCSC) lines that showed prolonged maintenance over 20 serial passages in vitro, while retaining their tumor-initiating biological properties. We then deciphered the intrinsic mechanism using analyses of mRNA expression array profiles. It has been determined that pro-opiomelanocortin (POMC) is closely related with protein phosphorylation mediated by G-protein-coupled estrogen receptor (GPER) in BCSC. Following, knockdown of POMC inhibits properties of mammosphere formation, CD44+CD24-population, CD44 expression, and clonogenicity ability in BCSC. We found that inhibition of POMC attenuates phosphorylation of AKT2 and GSK3β in BCSC. Further in vivo investigations demonstrated that POMC interference regulates proliferation of BCSC-bearing tumors. Combination of the clinical results that POMC positive expression is frequently upregulated in human breast cancer and POMC positivity correlated with a poor prognosis, POMC is a potential therapeutic target for BCSC. In conclusion, we have successfully established two long-term-cultured BCSC from clinical specimens. We further indicated that POMC acts as a potential therapeutic target and prognostic marker for future treatment of BCSC.
authors.affiliation: Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.|Department of Oncology, The Affiliated Xiang'an Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, China.|Department of Surgery, Fujian Provincial Tumor Hospital, Fuzhou, 350014, China.
authors.forename: Xiaoti
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Physiology, Zhongshan medical school, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Weiyu
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Oncology, The Affiliated Xiang'an Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, China.|Department of Emergency, Fujian Provincial 2nd People's Hospital, Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, 350000, China.
authors.forename: Fengqin
authors.initials: F
authors.lastname: Wei
authors.affiliation: Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.|Department of Molecular and Cellular Biochemistry, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
authors.forename: Xiaoming
authors.identifier: 0000-0003-3453-533X
authors.initials: X
authors.lastname: Xie
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D002273:Carcinogens; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011333:Pro-Opiomelanocortin; C494921:AKT2 protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: POMC; breast cancer; cancer stem cells; prognostic marker; therapeutic target