title: Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.
abstract: Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan-Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of PYCR1 mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both PYCR1 mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher PYCR1 mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For in vitro studies, inhibition of PYCR1 by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, PYCR1 might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.
authors.affiliation: Shaoxing Women and Children's Hospital, Shaoxing, Zhejiang 312000, China.|City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Ding
authors.affiliation: City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Kuo
authors.affiliation: Ph.D. Program of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan, ROC.
authors.forename: Leila
authors.initials: L
authors.lastname: Su
authors.affiliation: Pathology Department, Loma Linda University Medical Center, Loma Linda, CA 92354, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.affiliation: General Medicine Division, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.|Sino-American Cancer Foundation, 4978 Santa Anita Ave, Suite #104, Temple City, CA 91780, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Luh
authors.affiliation: Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310009, China and.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Sino-American Cancer Foundation, 4978 Santa Anita Ave, Suite #104, Temple City, CA 91780, USA.
authors.forename: Jianghai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Sino-American Cancer Foundation, 4978 Santa Anita Ave, Suite #104, Temple City, CA 91780, USA.
authors.forename: Tiffany G
authors.initials: TG
authors.lastname: Lin
authors.affiliation: City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Cancer Institute, Zhejiang University, Hangzhou, Zhejiang 310009, China and.
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Ph.D. Program of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan, ROC.|Sino-American Cancer Foundation, 4978 Santa Anita Ave, Suite #104, Temple City, CA 91780, USA.|California Cancer Institute, Temple City, CA 91007, USA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Ph.D. Program of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan, ROC.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D011762:Pyrroline Carboxylate Reductases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D014408:Biomarkers, Tumor; D011762:Pyrroline Carboxylate Reductases; D011960:Receptors, Estrogen; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase