title: Progesterone and Src family inhibitor PP1 synergistically inhibit cell migration and invasion of human basal phenotype breast cancer cells.
abstract: Basal phenotype breast cancer is one of the most aggressive breast cancers that frequently metastasize to brain. The role of sex hormones and their receptors in development of this disease is largely unclear. We demonstrated that mPRα was expressed at a moderate level in a brain metastatic BPBC cell line MB231Br, which was derived from the parent mPRα undetectable MB231 cells. It functioned as an essential mediator for progesterone induced inhibitory effects on cell migration of MB231Br and, when coincubated with PP1, synergistically enhanced the progesterone's inhibitory effect on cell migration and invasion in vitro. Progesterone and PP1 cotreatment induced a cascade of molecular signaling events, such as dephosphorylation of FAK, downregulation of MMP9, VEGF, and KCNMA1 expressions. Our in vitro study demonstrated that mPRα was expressed and functioned as an essential mediator for progesterone induced inhibitory effects on cell migration and invasion in BPBC cells. This inhibitory effect was enhanced by PP1 via FAK dephosphorylation, MMP9, VEGF, and KCNMA1 downregulation mechanisms. Our study provides a new clue toward the development of novel promising agents and pathways for inhibiting nuclear hormonal receptor-negative and endocrine-resistant breast cancers.
authors.affiliation: Department of Geriatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China ; Department of Respiratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China ; Laboratory of Cancer Experimental Therapy, Atlanta Research & Educational Foundation (151F), Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA.
authors.forename: Mingxuan
authors.identifier: 0000-0002-0866-8983
authors.initials: M
authors.lastname: Xie
authors.affiliation: Laboratory of Cancer Experimental Therapy, Atlanta Research & Educational Foundation (151F), Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA ; Department of Oncology, Shanghai Seventh People's Hospital, 358 Datong Road, Pudong New District, Shanghai 200137, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Respiratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratory of Cancer Experimental Therapy, Atlanta Research & Educational Foundation (151F), Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA.
authors.forename: Lindsey O
authors.initials: LO
authors.lastname: Gainey
authors.affiliation: Department of Geriatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China ; Department of Respiratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Medical Service, Atlanta VA Medical Center and Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Decatur, GA 30033, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Nanes
authors.affiliation: Department of Oncology, Shanghai Seventh People's Hospital, 358 Datong Road, Pudong New District, Shanghai 200137, China.
authors.forename: Anji
authors.initials: A
authors.lastname: Hou
authors.affiliation: Laboratory of Cancer Experimental Therapy, Atlanta Research & Educational Foundation (151F), Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033, USA.
authors.forename: Shaojin
authors.initials: S
authors.lastname: You
authors.affiliation: Department of Geriatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China ; Department of Respiratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Chen
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011374:Progesterone; D019061:src-Family Kinases