Prognostic significance of PLIN1 expression in human breast cancer

Breast cancer is a heterogeneous disease associated with diverse clinical, biological and molecular features, presenting huge challenges for prognosis and treatment. Here we found that perilipin-1 (PLIN1) mRNA expression is significantly downregulated in human breast cancer. Kaplan-Meier analysis indicated that patients presenting with reduced PLIN1 expression exhibited poorer overall metastatic relapse-free survival (p = 0.03). Further Cox proportional hazard models analysis revealed that the reduced expression of PLIN1 is an independent predictor of overall survival in estrogen receptor positive (p < 0.0001, HR = 0.87, 95% CI = 0.81–0.92, N = 3,600) and luminal A-subtype (p = 0.02, HR = 0.88, 95% CI = 0.78–0.98, N = 1,469) breast cancer patients. We also demonstrated that the exogenous expression of PLIN1 in human breast cancer MCF-7 and MDA-MB-231 cells significantly inhibits cell proliferation, migration, invasion and in vivo tumorigenesis in mice. Together, these data provide novel insights into a prognostic significance of PLIN1 in human breast cancer and reveal a potentially new gene therapy target for breast cancer.

[1]  Robert V Farese,et al.  Cellular fatty acid metabolism and cancer. , 2013, Cell metabolism.

[2]  M. Campone,et al.  bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer , 2012, Breast Cancer Research and Treatment.

[3]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[4]  C. Ahn,et al.  Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1 , 2016, Lipids in Health and Disease.

[5]  E. Winer,et al.  Follow-up care of patients with breast cancer. , 2007, Breast.

[6]  Jing Wang,et al.  Epithelial–Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma , 2016, Clinical Cancer Research.

[7]  M. Welte,et al.  PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. , 2009, Biochimica et biophysica acta.

[8]  Richard G. W. Anderson,et al.  Chinese Hamster Ovary K2 Cell Lipid Droplets Appear to Be Metabolic Organelles Involved in Membrane Traffic* , 2004, Journal of Biological Chemistry.

[9]  Breast Cancer Stage, Surgery, and Survival Statistics for Idaho’s National Breast and Cervical Cancer Early Detection Program Population, 2004–2012 , 2015, Preventing chronic disease.

[10]  T. Natsume,et al.  Proteomic profiling of lipid droplet proteins in hepatoma cell lines expressing hepatitis C virus core protein. , 2006, Journal of biochemistry.

[11]  J. Galván,et al.  COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression , 2015, Tumor Biology.

[12]  Yingming Zhao,et al.  Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation. , 2007, Journal of proteome research.

[13]  Brittany Anderton,et al.  Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer , 2016, Nature Medicine.

[14]  Tae Hyun Kim,et al.  Locoregional Recurrence by Tumor Biology in Breast Cancer Patients after Preoperative Chemotherapy and Breast Conservation Treatment , 2016, Cancer research and treatment : official journal of Korean Cancer Association.

[15]  Jun Dai,et al.  Pygo2 functions as a prognostic factor for glioma due to its up-regulation of H3K4me3 and promotion of MLL1/MLL2 complex recruitment , 2016, Scientific Reports.

[16]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Fackler,et al.  Biomarker Modulation following Short-Term Vorinostat in Women with Newly Diagnosed Primary Breast Cancer , 2013, Clinical Cancer Research.

[18]  Lin Zhang,et al.  The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis , 2016, Nature Communications.

[19]  K. Nakajima,et al.  Remnant lipoproteins induced proliferation of human prostate cancer cell, PC-3 but not LNCaP, via low density lipoprotein receptor. , 2009, Cancer epidemiology.

[20]  James B. Brown,et al.  Sparse linear modeling of next-generation mRNA sequencing (RNA-Seq) data for isoform discovery and abundance estimation , 2011, Proceedings of the National Academy of Sciences.

[21]  T. Okumura Role of lipid droplet proteins in liver steatosis , 2011, Journal of Physiology and Biochemistry.

[22]  Tatiana Popova,et al.  Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications. , 2016, Cancer research.

[23]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[24]  Y. Lei,et al.  Recent progress in HER2 associated breast cancer. , 2015, Asian Pacific journal of cancer prevention : APJCP.

[25]  D. Jeffe,et al.  Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. , 2009, Journal of the American College of Surgeons.

[26]  H. Jäckle,et al.  Characterization of the Drosophila Lipid Droplet Subproteome*S , 2006, Molecular & Cellular Proteomics.

[27]  A. Kimmel,et al.  Perilipin A Increases Triacylglycerol Storage by Decreasing the Rate of Triacylglycerol Hydrolysis* , 2000, The Journal of Biological Chemistry.

[28]  D. Neuberg,et al.  Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Validation of UBE2C protein as a prognostic marker in node-positive breast cancer , 2009, British Journal of Cancer.

[31]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[32]  L. Shapiro,et al.  Proteomic Analysis of Proteins Associated with Lipid Droplets of Basal and Lipolytically Stimulated 3T3-L1 Adipocytes* , 2004, Journal of Biological Chemistry.

[33]  J. Hagberg,et al.  Endurance exercise training effects on body fatness, VO2max, HDL-C subfractions, and glucose tolerance are influenced by a PLIN haplotype in older Caucasians. , 2010, Journal of applied physiology.

[34]  R. Karnes,et al.  P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth , 2016, Oncotarget.

[35]  David G. Robinson,et al.  A nested parallel experiment demonstrates differences in intensity-dependence between RNA-seq and microarrays , 2014, bioRxiv.

[36]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[37]  Aleksandra M. Michalowska,et al.  Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer. , 2006, Cancer research.

[38]  Mats Lambe,et al.  Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories , 2016, Cancer medicine.

[39]  R. Ahima,et al.  Pathophysiology of lipid droplet proteins in liver diseases. , 2016, Experimental cell research.

[40]  B. Williams,et al.  Mapping and quantifying mammalian transcriptomes by RNA-Seq , 2008, Nature Methods.

[41]  A. Alsaif Breast cancer recurrence after sentinel lymph node biopsy , 2015, Pakistan journal of medical sciences.

[42]  Stephen L. Abrams,et al.  Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. , 2006, Advances in enzyme regulation.