The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells

Menendez, Javier A.; Vellon, Luciano; Espinoza, Ingrid; Lupu, Ruth

doi:10.18632/oncoscience.314

Title: The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells

Journal Article · Fri Jul 22 00:00:00 EDT 2016 · Oncoscience

DOI:https://doi.org/10.18632/oncoscience.314· OSTI ID:1629907

Menendez, Javier A. ^[1]; Vellon, Luciano ^[2]; Espinoza, Ingrid ^[3]; Lupu, Ruth ^[4]

Catalan Institute of Oncology, Girona, Catalonia (Spain); Girona Biomedical Research Inst. (IDIBGI), Girona (Spain)
CONICET-Laboratorio de Immunohematología, Buenos Aires (Argentina)
University of Mississippi, Jackson, MS (United States)
Mayo Clinic, Rochester, MN (United States); Mayo Clinic Cancer Center, Rochester, MN (United States)

The angiogenic inducer CCN1 (Cysteine-rich 61, CYR61) is differentially activated in metastatic breast carcinomas. However, little is known about the precise mechanisms that underlie the pro-metastatic actions of CCN1. Here, we investigated the impact of CCN1 expression on fatty acid synthase (FASN), a metabolic oncogene thought to provide cancer cells with proliferative and survival advantages. Forced expression of CCN1 in MCF-7 cells robustly up-regulated FASN protein expression and also significantly increased FASN gene promoter activity 2- to 3-fold, whereas deletion of the sterol response element-binding protein (SREBP) binding site in the FASN promoter completely abrogated CCN1-driven transcriptional activation. Pharmacological blockade of MAPK or PI-3’K activation similarly prevented the ability of CCN1 to induce FASN gene activation. Pharmacological inhibition of FASN activity with the mycotoxin cerulenin or the small compound C75 reversed CCN1-induced acquisition of estrogen independence and resistance to hormone therapies such as tamoxifen and fulvestrant in anchorage-independent growth assays. This study uncovers FASN-dependent endogenous lipogenesis as a new mechanism controlling the metastatic phenotype promoted by CCN1. Because estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer, this previously unrecognized CCN1-driven lipogenic phenotype represents a novel metabolic target to clinically manage metastatic disease progression.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Mayo Clinic, Rochester, MN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; Department of Defense (DoD); National Institutes of Health (NIH); Ministerio de Ciencia e Innovación; Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)

Grant/Contract Number:: SC0012379; W81XWH-06-1-0703; R01-CA118975; AC03-76SF00098; SAF2012-38914; 2014 SGR229

OSTI ID:: 1629907

Journal Information:: Oncoscience, Vol. 3, Issue 7-8; ISSN 2331-4737

Publisher:: Impact Journals, LLCCopyright Statement

Country of Publication:: United States

Language:: English

References (56)

Pharmacological Inhibitors of Fatty Acid Synthase (FASN)-Catalyzed Endogenous Fatty Acid Biogenesis: A New Family of Anti-Cancer Agents? Lupu, Ruth; Menendez, Javier Current Pharmaceutical Biotechnology, Vol. 7, Issue 6 https://doi.org/10.2174/138920106779116928	journal	December 2006
Modulation of breast cancer progression and differentiation by thegp30/neregulin Staebler, A.; Sommers, C.; Mueller, S. C. Breast Cancer Research and Treatment, Vol. 31, Issue 2-3 https://doi.org/10.1007/BF00666151	journal	January 1994
Antiangiogenic Resistance: Novel Angiogenesis Axes Uncovered by Antiangiogenic Therapies Research Jiménez-Valerio, Gabriela; Casanovas, Oriol Current Drug Targets, Vol. 17, Issue 15 https://doi.org/10.2174/1389450117666160301101425	journal	October 2016
Metabolic alterations and targeted therapies in prostate cancer Flavin, Richard; Zadra, Giorgia; Loda, Massimo The Journal of Pathology, Vol. 223, Issue 2 https://doi.org/10.1002/path.2809	journal	November 2010
Oncogenic properties of the endogenous fatty acid metabolism: molecular pathology of fatty acid synthase in cancer cells Menendez, Javier A.; Lupu, Ruth Current Opinion in Clinical Nutrition & Metabolic Care, Vol. 9, Issue 4 https://doi.org/10.1097/01.mco.0000232893.21050.15	journal	July 2006
Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis Dean, Richard A.; Butler, Georgina S.; Hamma-Kourbali, Yamina Molecular and Cellular Biology, Vol. 27, Issue 24 https://doi.org/10.1128/MCB.00821-07	journal	December 2007
Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype? Le Du, Fanny; Eckhardt, Bedrich L.; Lim, Bora Oncotarget, Vol. 6, Issue 15 https://doi.org/10.18632/oncotarget.3849	journal	May 2015
The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34+ progenitor cells: potential role in angiogenesis and endothelial regeneration Grote, Karsten; Salguero, Gustavo; Ballmaier, Matthias Blood, Vol. 110, Issue 3 https://doi.org/10.1182/blood-2006-07-036202	journal	August 2007
Antiangiogenic Therapies: Going beyond Their Limits Moserle, Lidia; Jiménez-Valerio, Gabriela; Casanovas, Oriol Cancer Discovery, Vol. 4, Issue 1 https://doi.org/10.1158/2159-8290.CD-13-0199	journal	January 2014
Sterol Regulatory Element-Binding Protein–1/Fatty Acid Synthase Involvement in Proliferation Inhibition and Apoptosis Promotion Induced by Progesterone in Endometrial Cancer Qiu, Chunping; Dongol, Samina; Lv, Qing-tao International Journal of Gynecologic Cancer, Vol. 23, Issue 9 https://doi.org/10.1097/IGC.0000000000000004	journal	November 2013
Molecularly targeted therapies for metastatic triple-negative breast cancer Bayraktar, Soley; Glück, Stefan Breast Cancer Research and Treatment, Vol. 138, Issue 1 https://doi.org/10.1007/s10549-013-2421-5	journal	January 2013
Lipogenesis in cancer progression (Review) Mounier, Catherine; Bouraoui, Lamia; Rassart, Eric International Journal of Oncology, Vol. 45, Issue 2 https://doi.org/10.3892/ijo.2014.2441	journal	May 2014
αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer Vellon, Luciano; Menendez, Javier A.; Lupu, Ruth Oncogene, Vol. 24, Issue 23 https://doi.org/10.1038/sj.onc.1208452	journal	March 2005
Functional domains of CCN1 (Cyr61) regulate breast cancer progression O'Kelly, James; Chung, Alice; Lemp, Nathan International Journal of Oncology https://doi.org/10.3892/ijo.33.1.59	journal	July 2008
The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives. Men√©ndez, J. A.; Mehmi, I.; Griggs, D. W. Endocrine-related cancer https://doi.org/10.1677/erc.0.0100141	journal	June 2003
The nutritional phenome of EMT-induced cancer stem-like cells Cuyàs, Elisabet; Corominas-Faja, Bruna; Menendez, Javier A. Oncotarget, Vol. 5, Issue 12 https://doi.org/10.18632/oncotarget.2147	journal	June 2014
Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway Swinnen, Johannes V.; Heemers, Hannelore; Deboel, Ludo Oncogene, Vol. 19, Issue 45 https://doi.org/10.1038/sj.onc.1203889	journal	October 2000
CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth Babic, Alexander M.; Kireeva, Maria L.; Kolesnikova, Tatiana V. Proceedings of the National Academy of Sciences, Vol. 95, Issue 11 https://doi.org/10.1073/pnas.95.11.6355	journal	May 1998
Anti-Cancer Drugs Targeting Fatty Acid Synthase (FAS) R. Pandey, Puspa; Liu, Wen; Xing, Fei Recent Patents on Anti-Cancer Drug Discovery, Vol. 7, Issue 2 https://doi.org/10.2174/157489212799972891	journal	March 2012
Fatty acid synthase as a potential therapeutic target in cancer Flavin, Richard; Peluso, Stephane; Nguyen, Paul L. Future Oncology, Vol. 6, Issue 4 https://doi.org/10.2217/fon.10.11	journal	April 2010
An Angiogenic Switch in Breast Cancer Involves Estrogen and Soluble Vascular Endothelial Growth Factor Receptor 1 Elkin, M.; Orgel, A.; Kleinman, H. K. JNCI Journal of the National Cancer Institute, Vol. 96, Issue 11 https://doi.org/10.1093/jnci/djh140	journal	June 2004
Coordinate regulation of lipogenic gene expression by androgens: Evidence for a cascade mechanism involving sterol regulatory element binding proteins Swinnen, Johannes V.; Ulrix, William; Heyns, Walter Proceedings of the National Academy of Sciences, Vol. 94, Issue 24 https://doi.org/10.1073/pnas.94.24.12975	journal	November 1997
P2-05-01: Acquired Tamoxifen Resistance Promotes Angiogenic Responses in ER+ Breast Cancer Cells. Hayes, E.; Smith, C.; Nicholson, Ri Cancer Research, Vol. 71, Issue 24_Supplement https://doi.org/10.1158/0008-5472.SABCS11-P2-05-01	journal	December 2011
Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells. Garcia, M.; Derocq, D.; Freiss, G. Proceedings of the National Academy of Sciences, Vol. 89, Issue 23 https://doi.org/10.1073/pnas.89.23.11538	journal	December 1992
Breast Cancer Xie, Dong; Miller, Carl W.; O'Kelly, James Journal of Biological Chemistry, Vol. 276, Issue 17 https://doi.org/10.1074/jbc.M009755200	journal	April 2001
Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis Menendez, Javier A.; Lupu, Ruth Nature Reviews Cancer, Vol. 7, Issue 10 https://doi.org/10.1038/nrc2222	journal	October 2007
Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: Molecular mechanisms and therapeutic perspectives Menendez, Javier A. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Vol. 1801, Issue 3 https://doi.org/10.1016/j.bbalip.2009.09.005	journal	March 2010
Lipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids Zaidi, Nousheen; Lupien, Leslie; Kuemmerle, Nancy B. Progress in Lipid Research, Vol. 52, Issue 4 https://doi.org/10.1016/j.plipres.2013.08.005	journal	October 2013
CCN proteins and cancer: two to tango Bleau, Anne-Marie, Frontiers in Bioscience, Vol. 10, Issue 1-3 https://doi.org/10.2741/1594	journal	January 2005
A novel CYR61-triggered ‘CYR61-αvβ3 integrin loop’ regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway Menendez, Javier A.; Vellon, Luciano; Mehmi, Inderjit Oncogene, Vol. 24, Issue 5 https://doi.org/10.1038/sj.onc.1208238	journal	December 2004
Cyr61 promotes breast tumorigenesis and cancer progression Tsai, Miaw-Sheue; Bogart, Daphne F.; Castañeda, Jessica M. Oncogene, Vol. 21, Issue 53 https://doi.org/10.1038/sj.onc.1205682	journal	November 2002
Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling Clarke, Robert; Liu, Minetta C.; Bouker, Kerrie B. Oncogene, Vol. 22, Issue 47 https://doi.org/10.1038/sj.onc.1206937	journal	October 2003
Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development Ivkovic, Sanja; Yoon, Byeong S.; Popoff, Steven N. Development, Vol. 130, Issue 12 https://doi.org/10.1242/dev.00505	journal	June 2003
Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance van Agthoven, Ton; Sieuwerts, Anieta M.; Meijer-van Gelder, Marion E. Journal of Clinical Oncology, Vol. 27, Issue 4 https://doi.org/10.1200/JCO.2008.17.1462	journal	February 2009
Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer Zaytseva, Yekaterina Y.; Rychahou, Piotr G.; Gulhati, Pat Cancer Research, Vol. 72, Issue 6 https://doi.org/10.1158/0008-5472.CAN-11-4057	journal	March 2012
Activation of Androgen Receptor, Lipogenesis, and Oxidative Stress Converged by SREBP-1 Is Responsible for Regulating Growth and Progression of Prostate Cancer Cells Huang, Wen-Chin; Li, Xiangyan; Liu, Jian Molecular Cancer Research, Vol. 10, Issue 1 https://doi.org/10.1158/1541-7786.MCR-11-0206	journal	January 2012
Vascular Endothelial Growth Factor Secreted by Activated Stroma Enhances Angiogenesis and Hormone-Independent Growth of Estrogen Receptor–Positive Breast Cancer Pinto, Mauricio P.; Badtke, Melanie M.; Dudevoir, Michelle L. Cancer Research, Vol. 70, Issue 7 https://doi.org/10.1158/0008-5472.CAN-09-4373	journal	March 2010
Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer Zaytseva, Yekaterina Y.; Elliott, Victoria A.; Rychahou, Piotr Carcinogenesis, Vol. 35, Issue 6 https://doi.org/10.1093/carcin/bgu042	journal	February 2014
Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets Jun, Joon-Il; Lau, Lester F. Nature Reviews Drug Discovery, Vol. 10, Issue 12 https://doi.org/10.1038/nrd3599	journal	December 2011
Androgens Stimulate Lipogenic Gene Expression in Prostate Cancer Cells by Activation of the Sterol Regulatory Element-Binding Protein Cleavage Activating Protein/Sterol Regulatory Element-Binding Protein Pathway Heemers, Hannelore; Maes, Bart; Foufelle, Fabienne Molecular Endocrinology, Vol. 15, Issue 10 https://doi.org/10.1210/mend.15.10.0703	journal	October 2001
Expression and regulation of Cyr61 in human breast cancer cell lines Tsai, Miaw-Sheue; Bogart, Daphne F.; Li, Patricia Oncogene, Vol. 21, Issue 6 https://doi.org/10.1038/sj.onc.1205131	journal	January 2002
Identification of a Novel Integrin αvβ3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells Chen, Ningyu; Leu, Shr-Jeng; Todorović, Viktor Journal of Biological Chemistry, Vol. 279, Issue 42 https://doi.org/10.1074/jbc.M406813200	journal	October 2004
Blocking Lipid Synthesis Overcomes Tumor Regrowth and Metastasis after Antiangiogenic Therapy Withdrawal Sounni, Nor Eddine; Cimino, Jonathan; Blacher, Silvia Cell Metabolism, Vol. 20, Issue 2 https://doi.org/10.1016/j.cmet.2014.05.022	journal	August 2014
Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c Yang, Y. u-A. n.; Morin, Patrice J.; Han, Wan Fang Experimental Cell Research, Vol. 282, Issue 2 https://doi.org/10.1016/s0014-4827(02)00023-x	journal	January 2003
Triple-negative breast cancer: disease entity or title of convenience? Carey, Lisa; Winer, Eric; Viale, Giuseppe Nature Reviews Clinical Oncology, Vol. 7, Issue 12 https://doi.org/10.1038/nrclinonc.2010.154	journal	September 2010
The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts Chen, Chih-Chiun; Mo, Fan-E; Lau, Lester F. Journal of Biological Chemistry, Vol. 276, Issue 50 https://doi.org/10.1074/jbc.m107666200	journal	December 2001
Matrix Metalloproteinases Cleave Connective Tissue Growth Factor and Reactivate Angiogenic Activity of Vascular Endothelial Growth Factor 165 Hashimoto, Gakuji; Inoki, Isao; Fujii, Yutaka Journal of Biological Chemistry, Vol. 277, Issue 39 https://doi.org/10.1074/jbc.m201674200	journal	September 2002
Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion Kireeva, M. L.; Mo, F. E.; Yang, G. P. Molecular and Cellular Biology, Vol. 16, Issue 4 https://doi.org/10.1128/mcb.16.4.1326	journal	April 1996
Fisp12/Mouse Connective Tissue Growth Factor Mediates Endothelial Cell Adhesion and Migration through Integrin α _v β ₃ , Promotes Endothelial Cell Survival, and Induces Angiogenesis In Vivo Babic, Alexander M.; Chen, Chih-Chiun; Lau, Lester F. Molecular and Cellular Biology, Vol. 19, Issue 4 https://doi.org/10.1128/mcb.19.4.2958	journal	April 1999
Fatty Acid Synthase Gene Is Up-regulated by Hypoxia via Activation of Akt and Sterol Regulatory Element Binding Protein-1 Furuta, Eiji; Pai, Sudha K.; Zhan, Rui Cancer Research, Vol. 68, Issue 4 https://doi.org/10.1158/0008-5472.can-07-2489	journal	February 2008
Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer Rhodes, Lyndsay V.; Short, Sarah P.; Neel, Nicole F. Cancer Research, Vol. 71, Issue 2 https://doi.org/10.1158/0008-5472.can-10-3185	journal	January 2011
New Strategies for Triple-Negative Breast Cancer—Deciphering the Heterogeneity Mayer, Ingrid A.; Abramson, Vandana G.; Lehmann, Brian D. Clinical Cancer Research, Vol. 20, Issue 4 https://doi.org/10.1158/1078-0432.ccr-13-0583	journal	February 2014
Molecular Pathways: Fatty Acid Synthase Jones, Suzanne F.; Infante, Jeffrey R. Clinical Cancer Research, Vol. 21, Issue 24 https://doi.org/10.1158/1078-0432.ccr-15-0126	journal	December 2015
Enhancement of vascular endothelial growth factor–mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression Kim, Mi Ra; Choi, Hong Seok; Yang, Jin Won Molecular Cancer Therapeutics, Vol. 8, Issue 8 https://doi.org/10.1158/1535-7163.mct-08-1061	journal	August 2009
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi Journal of Clinical Investigation, Vol. 121, Issue 7 https://doi.org/10.1172/jci45014	journal	July 2011
Triple-Negative Breast Cancer: An Unmet Medical Need Hudis, Clifford A.; Gianni, Luca The Oncologist, Vol. 16, Issue S1 https://doi.org/10.1634/theoncologist.2011-s1-01	journal	January 2011

Cited By (1)

Fatty acids distribution and content in oral squamous cell carcinoma tissue and its adjacent microenvironment Halczy-Kowalik, Ludmiła; Drozd, Arleta; Stachowska, Ewa PLOS ONE, Vol. 14, Issue 6 https://doi.org/10.1371/journal.pone.0218246	journal	June 2019

Similar Records

Cyr61 promotes breast tumorigenesis and cancer progression

Journal Article · Wed Jan 16 00:00:00 EST 2002 · Oncogene · OSTI ID:1629907

Tsai, Miaw-Sheue; Bogart, Daphne F; Castaneda, Jessica M; +2 more

The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells

Journal Article · Wed Oct 15 00:00:00 EDT 2008 · Experimental Cell Research · OSTI ID:1629907

Yang, Yu; Yu, Gao; Wang, Hong; +7 more

Theanaphthoquinone inhibits fatty acid synthase expression in EGF-stimulated human breast cancer cells via the regulation of EGFR/ErbB-2 signaling

Journal Article · Mon Jan 15 00:00:00 EST 2007 · Toxicology and Applied Pharmacology · OSTI ID:1629907

Weng, M -S; Ho, C -T; Ho, Y -S; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CCN1
CYR61
fatty acid synthase
breast cancer
metastasis

Title: The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells

Citation Formats

References (56)

Cited By (1)

Similar Records

Related Subjects