Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2010

Open Access 01-12-2010 | Research article

Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells

Authors: Quanri Jin, Linda X Yuan, Delphine Boulbes, Jong Min Baek, Ying Nai Wang, Daniel Gomez-Cabello, David H Hawke, Sai Ching Yeung, Mong Hong Lee, Gabriel N Hortobagyi, Mien Chie Hung, Francisco J Esteva

Published in: Breast Cancer Research | Issue 6/2010

Login to get access

Abstract

Introduction

The human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in breast cancer. Heterodimerization of HER2 with other HER family members results in enhanced tyrosine phosphorylation and activation of signal transduction pathways. HER2 overexpression increases the translation of fatty acid synthase (FASN), and FASN overexpression markedly increases HER2 signaling, which results in enhanced cell growth. However, the molecular mechanism and regulation of HER2 and FASN interaction are not well defined. Lapatinib is a small-molecule tyrosine kinase inhibitor that blocks phosphorylation of the epidermal growth factor receptor and HER2 in breast cancer cells, resulting in apoptosis. We hypothesized that FASN is directly phosphorylated by HER2, resulting in enhanced signaling and tumor progression in breast cancer cells.

Methods

Using mass spectrometry, we identified FASN as one of the proteins that is dephosphorylated by lapatinib in SKBR3 breast cancer cells. Immunofluorescence, immunoprecipitation, Western blotting, a kinase assay, a FASN enzymatic activity assay, an invasion assay, a cell viability assay and zymography were used to determine the role of FASN phosphorylation in invasion of SKBR3 and BT474 cells. The FASN inhibitor C75 and small interfering RNA were used to downregulate FASN expression and/or activity.

Results

Our data demonstrated that FASN is phosphorylated when it is in complex with HER2. FASN phosphorylation was induced by heregulin in HER2-overexpressing SKBR3 and BT474 breast cancer cells. Heregulin-induced FASN phosphorylation resulted in increased FASN enzymatic activity, which was inhibited by lapatinib. The FASN inhibitor C75 suppressed FASN activity by directly inhibiting HER2 and FASN phosphorylation. Blocking FASN phosphorylation and activity by lapatinib or C75 suppressed the activity of matrix metallopeptidase 9 and inhibited invasion of SKBR3 and BT474 cells.

Conclusions

FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.
Appendix
Available only for authorised users
Literature
1.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235: 177-182. 10.1126/science.3798106.CrossRefPubMed
2.
Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN: Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002, 20: 1800-1808. 10.1200/JCO.2002.07.058.CrossRefPubMed
3.
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006, 355: 2733-2743. 10.1056/NEJMoa064320.CrossRefPubMed
4.
Johnston S, Pippen J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009, 27: 5538-5546. 10.1200/JCO.2009.23.3734.CrossRefPubMed
5.
Esteva FJ, Yu D, Hung MC, Hortobagyi GN: Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol. 7: 98-107. 10.1038/nrclinonc.2009.216.
6.
Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL: Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem. 1994, 269: 14661-14665.PubMed
7.
Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A: Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. Embo J. 1995, 14: 4267-4275.PubMedPubMedCentral
8.
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, et al: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985, 230: 1132-1139. 10.1126/science.2999974.CrossRefPubMed
9.
Xie Y, Li K, Hung MC: Tyrosine phosphorylation of Shc proteins and formation of Shc/Grb2 complex correlate to the transformation of NIH3T3 cells mediated by the point-mutation activated neu. Oncogene. 1995, 10: 2409-2413.PubMed
10.
Jin Q, Esteva FJ: Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia. 2008, 13: 485-498. 10.1007/s10911-008-9107-3.CrossRefPubMed
11.
Kourtidis A, Srinivasaiah R, Carkner RD, Brosnan MJ, Conklin DS: Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity. Breast Cancer Res. 2009, 11: R16-10.1186/bcr2240.CrossRefPubMedPubMedCentral
12.
Yoon S, Lee MY, Park SW, Moon JS, Koh YK, Ahn YH, Park BW, Kim KS: Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem. 2007, 282: 26122-26131. 10.1074/jbc.M702854200.CrossRefPubMed
13.
Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR: Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA. 1994, 91: 6379-6383. 10.1073/pnas.91.14.6379.CrossRefPubMedPubMedCentral
14.
Vazquez-Martin A, Colomer R, Brunet J, Lupu R, Menendez JA: Overexpression of fatty acid synthase gene activates HER1/HER2 tyrosine kinase receptors in human breast epithelial cells. Cell Prolif. 2008, 41: 59-85. 10.1111/j.1365-2184.2007.00498.x.CrossRefPubMed
15.
Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL, Townsend CA: Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci USA. 2000, 97: 3450-3454. 10.1073/pnas.050582897.CrossRefPubMedPubMedCentral
16.
Kumar-Sinha C, Ignatoski KW, Lippman ME, Ethier SP, Chinnaiyan AM: Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res. 2003, 63: 132-139.PubMed
17.
Menendez JA: Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. Biochim Biophys Acta. 1801: 381-391.
18.
Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R: Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA. 2004, 101: 10715-10720. 10.1073/pnas.0403390101.CrossRefPubMedPubMedCentral
19.
Menendez JA, Vellon L, Lupu R: Targeting fatty acid synthase-driven lipid rafts: a novel strategy to overcome trastuzumab resistance in breast cancer cells. Med Hypotheses. 2005, 64: 997-1001. 10.1016/j.mehy.2004.09.027.CrossRefPubMed
20.
Sabbisetti V, Di Napoli A, Seeley A, Amato AM, O'Regan E, Ghebremichael M, Loda M, Signoretti S: p63 promotes cell survival through fatty acid synthase. PLoS One. 2009, 4: e5877-10.1371/journal.pone.0005877.CrossRefPubMedPubMedCentral
21.
Grunt TW, Wagner R, Grusch M, Berger W, Singer CF, Marian B, Zielinski CC, Lupu R: Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem Biophys Res Commun. 2009, 385: 454-459. 10.1016/j.bbrc.2009.05.085.CrossRefPubMed
22.
Menendez JA, Lupu R, Colomer R: Targeting fatty acid synthase: potential for therapeutic intervention in her-2/neu-overexpressing breast cancer. Drug News Perspect. 2005, 18: 375-385. 10.1358/dnp.2005.18.6.927929.CrossRefPubMed
23.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ: Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005, 65: 11118-11128. 10.1158/0008-5472.CAN-04-3841.CrossRefPubMed
24.
Jin Q, Feng L, Behrens C, Bekele BN, Wistuba II, Hong WK, Lee HY: Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin. Cancer Res. 2007, 67: 11630-11639. 10.1158/0008-5472.CAN-07-2401.CrossRefPubMed
25.
Jin Q, Menter DG, Mao L, Hong WK, Lee HY: Survivin expression in normal human bronchial epithelial cells: an early and critical step in tumorigenesis induced by tobacco exposure. Carcinogenesis. 2008, 29: 1614-1622. 10.1093/carcin/bgm234.CrossRefPubMedPubMedCentral
26.
Oh SH, Lee OH, Schroeder CP, Oh YW, Ke S, Cha HJ, Park RW, Onn A, Herbst RS, Li C, Lee HY: Antimetastatic activity of insulin-like growth factor binding protein-3 in lung cancer is mediated by insulin-like growth factor-independent urokinase-type plasminogen activator inhibition. Mol Cancer Ther. 2006, 5: 2685-2695. 10.1158/1535-7163.MCT-06-0142.CrossRefPubMed
27.
Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R: Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA. 2004, 101: 10715-10720. 10.1073/pnas.0403390101.CrossRefPubMedPubMedCentral
28.
Burris HA, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005, 23: 5305-5313. 10.1200/JCO.2005.16.584.CrossRefPubMed
29.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ: Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005, 65: 11118-11128. 10.1158/0008-5472.CAN-04-3841.CrossRefPubMed
30.
Puig T, Turrado C, Benhamú B, Aguilar H, Relat J, Ortega-Gutiérrez S, Casals G, Marrero PF, Urruticoechea A, Haro D, López-Rodríguez ML, Colomer R: Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity. Clin Cancer Res. 2009, 15: 7608-7615. 10.1158/1078-0432.CCR-09-0856.CrossRefPubMed
31.
Puig T, Vázquez-Martín A, Relat J, Pétriz J, Menéndez JA, Porta R, Casals G, Marrero PF, Haro D, Brunet J, Colomer R: Fatty acid metabolism in breast cancer cells: differential inhibitory effects of epigallocatechin gallate (EGCG) and C75. Breast Cancer Res Treat. 2008, 109: 471-479. 10.1007/s10549-007-9678-5.CrossRefPubMed
32.
Pizer ES, Jackisch C, Wood FD, Pasternack GR, Davidson NE, Kuhajda FP: Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res. 1996, 56: 2745-2747.PubMed
33.
Menendez JA, Mehmi I, Atlas E, Colomer R, Lupu R: Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. Int J Oncol. 2004, 24: 591-608.PubMed
34.
Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P, Yu D: Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene. 2001, 20: 8066-8074. 10.1038/sj.onc.1204944.CrossRefPubMed
35.
Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL: Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005, 24: 6213-6221. 10.1038/sj.onc.1208774.CrossRefPubMed
36.
Nahta R, Yuan LX, Du Y, Esteva FJ: Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther. 2007, 6: 667-674. 10.1158/1535-7163.MCT-06-0423.CrossRefPubMed
37.
Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramony Cajal S, Arribas J, Baselga J: Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009, 28: 803-814. 10.1038/onc.2008.432.CrossRefPubMed
38.
Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA: Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth. J Cell Physiol. 2011, 226: 52-57. 10.1002/jcp.22333.CrossRefPubMed
39.
Jackowski S, Wang J, Baburina I: Activity of the phosphatidylcholine biosynthetic pathway modulates the distribution of fatty acids into glycerolipids in proliferating cells. Biochim Biophys Acta. 2000, 1483: 301-315.CrossRefPubMed
40.
An Z, Wang H, Song P, Zhang M, Geng X, Zou MH: Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: a role for oxidant stress. J Biol Chem. 2007, 282: 26793-26801. 10.1074/jbc.M703701200.CrossRefPubMed
41.
Spector NL, Yarden Y, Smith B, Lyass L, Trusk P, Pry K, Hill JE, Xia W, Seger R, Bacus SS: Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc Natl Acad Sci USA. 2007, 104: 10607-10612. 10.1073/pnas.0701286104.CrossRefPubMedPubMedCentral
42.
Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS: Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle. 2008, 7: 1769-1775. 10.4161/cc.7.12.6016.CrossRefPubMed
43.
Landree LE, Hanlon AL, Strong DW, Rumbaugh G, Miller IM, Thupari JN, Connolly EC, Huganir RL, Richardson C, Witters LA, Kuhajda FP, Ronnett GV: C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J Biol Chem. 2004, 279: 3817-3827. 10.1074/jbc.M310991200.CrossRefPubMed
44.
Xue C, Liang F, Mahmood R, Vuolo M, Wyckoff J, Qian H, Tsai KL, Kim M, Locker J, Zhang ZY, Segall JE: ErbB3-dependent motility and intravasation in breast cancer metastasis. Cancer Res. 2006, 66: 1418-1426. 10.1158/0008-5472.CAN-05-0550.CrossRefPubMed
45.
Plowman GD, Green JM, Culouscou JM, Carlton GW, Rothwell VM, Buckley S: Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature. 1993, 366: 473-475. 10.1038/366473a0.CrossRefPubMed
46.
Kong A, Calleja V, Leboucher P, Harris A, Parker PJ, Larijani B: HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells. PLoS ONE. 2008, 3: e2881-10.1371/journal.pone.0002881.CrossRefPubMedPubMedCentral
47.
Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK, Lupu R: Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene. 2003, 22: 761-768. 10.1038/sj.onc.1206130.CrossRefPubMed
48.
Ellerbroek SM, Halbleib JM, Benavidez M, Warmka JK, Wattenberg EV, Stack MS, Hudson LG: Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res. 2001, 61: 1855-1861.PubMed
Metadata
Title
Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells
Authors
Quanri Jin
Linda X Yuan
Delphine Boulbes
Jong Min Baek
Ying Nai Wang
Daniel Gomez-Cabello
David H Hawke
Sai Ching Yeung
Mong Hong Lee
Gabriel N Hortobagyi
Mien Chie Hung
Francisco J Esteva
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2777

Other articles of this Issue 6/2010

Breast Cancer Research 6/2010 Go to the issue

Research article

Clinical significance of the nuclear receptor co-regulator DC-SCRIPT in breast cancer: an independent retrospective validation study

Viewpoint

Basal-like breast cancers: the phenotypic disparity between the cancer-initiating cells and tumor histology

Research article

A PALB2 mutation associated with high risk of breast cancer

Review

Key signaling nodes in mammary gland development and cancer: β-catenin

Research article

Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups

Research article

Inactivation of FBXW7/hCDC4-β expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits