title: Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.
abstract: Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Poage
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Department of Medicine and the Dan L. Duncan Cancer Center, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Den Hollander
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Hill
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Methodist Cancer Center, The Methodist Hospital Research Institute, Houston, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicine and the Dan L. Duncan Cancer Center, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Medicine and the Dan L. Duncan Cancer Center, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fuqua
authors.affiliation: Department of Medicine and the Dan L. Duncan Cancer Center, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kent Osborne
authors.affiliation: Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA. phbrown@mdanderson.org.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D054637:Dual-Specificity Phosphatases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D040081:Protein Array Analysis / Q000379:methods*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011960:Receptors, Estrogen; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases
keywords: MAPK pathways; Mouse xenograft; Phosphatase; TNBC