title: Protein phosphatase Mg2+/Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated-p53-induced signals.
abstract: We previously demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and -overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited for cancer prevention and therapy.
authors: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.|Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors: Shih-Hsin
authors: SH
authors: Tu
authors: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Yin-Ching
authors: YC
authors: Lin
authors: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.|Breast Center, Cathay General Hospital, Taipei, Taiwan.
authors: Chi-Cheng
authors: CC
authors: Huang
authors: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.|Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors: Po-Sheng
authors: PS
authors: Yang
authors: Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Hui-Wen
authors: HW
authors: Chang
authors: Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Chien-Hsi
authors: CH
authors: Chang
authors: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Surgery, En Chu Kong Hospital, New Taipei City, Taiwan.
authors: Chih-Hsiung
authors: CH
authors: Wu
authors: Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.|Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Li-Ching
authors: LC
authors: Chen
authors: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.|Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan.|School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors: Yuan-Soon
authors: YS
authors: Ho
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009367:Neoplasm Staging; D009538:Nicotine / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D009538:Nicotine; C459194:PPM1F protein, human; D010749:Phosphoprotein Phosphatases
keywords: breast cancer; p53; protein phosphatase Mg2+/Mn2+ dependent 1F; smoking; α9-nicotinic acetylcholine receptor