title: Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival.
abstract: Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared with estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR = 0.05) in TNBC compared with ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific siRNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1-S cell-cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients. Cancer Res; 76(7); 1942-53. ©2016 AACR.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Petra
authors.initials: P
authors.lastname: den Hollander
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rawls
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jamal
authors.initials: J
authors.lastname: Hill
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.affiliation: Methodist Cancer Center, The Methodist Hospital Research Institute, Houston, Texas.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. phbrown@mdanderson.org.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000401:mortality
chemical_list: D009363:Neoplasm Proteins; D010744:Phosphoric Monoester Hydrolases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases