Breast Cancer Research and Treatment

, Volume 138, Issue 1, pp 175–183 | Cite as

A proof of principle clinical trial to determine whether conjugated linoleic acid modulates the lipogenic pathway in human breast cancer tissue

  • Margit M. McGowan
  • Burton L. Eisenberg
  • Lionel D. Lewis
  • Heather M. Froehlich
  • Wendy A. Wells
  • Alan Eastman
  • Nancy B. Kuemmerle
  • Kari M. Rosenkrantz
  • Richard J. BarthJr.
  • Gary N. Schwartz
  • Zhongze Li
  • Tor D. Tosteson
  • Bernard B. BeaulieuJr.
  • William B. Kinlaw
Clinical Trial


Conjugated linoleic acid (CLA) is widely used as a “nutraceutical” for weight loss. CLA has anticancer effects in preclinical models, and we demonstrated in vitro that this can be attributed to the suppression of fatty acid (FA) synthesis. We tested the hypothesis that administration of CLA to breast cancer patients would inhibit expression of markers related to FA synthesis in tumor tissue, and that this would suppress tumor proliferation. Women with Stage I–III breast cancer were enrolled into an open label study and treated with CLA (1:1 mix of 9c,11t- and 10t,12c-CLA isomers, 7.5 g/d) for ≥10 days before surgery. Fasting plasma CLA concentrations measured pre- and post-CLA administration, and pre/post CLA tumor samples were examined by immunohistochemistry for Spot 14 (S14), a regulator of FA synthesis, FA synthase (FASN), an enzyme of FA synthesis, and lipoprotein lipase (LPL), the enzyme that allows FA uptake. Tumors were also analyzed for expression of Ki-67 and cleaved caspase 3. 24 women completed study treatment, and 23 tumors were evaluable for the primary endpoint. The median duration of CLA therapy was 12 days, and no significant toxicity was observed. S14 expression scores decreased (p = 0.003) after CLA administration. No significant change in FASN or LPL expression was observed. Ki-67 scores declined (p = 0.029), while cleaved caspase 3 staining was unaffected. Decrements in S14 or Ki-67 did not correlate with fasting plasma CLA concentrations at surgery. Breast tumor tissue expression of S14, but not FASN or LPL, was decreased after a short course of treatment with 7.5 g/day CLA. This was accompanied by reductions in the proliferation index. CLA consumption was well-tolerated and safe at this dose for up to 20 days. Overall, CLA may be a prototype compound to target fatty acid synthesis in breast cancers with a “lipogenic phenotype”.


Breast cancer Fatty acid Metabolism Conjugated linoleic acid 



Silver ion high pressure liquid chromatography


Conjugated linoleic acid


Fatty acid


Fatty acid synthase




Lipoprotein lipase


Spot 14, aka THRSP

Supplementary material

10549_2013_2446_MOESM1_ESM.doc (53 kb)
Supplementary material 1 (DOC 53 kb)
10549_2013_2446_MOESM2_ESM.doc (23 kb)
Supplementary material 2 (DOC 23 kb)


  1. 1.
    American Cancer Society, I(2012). Breast Cancer Facts & Figures 2011–2012. American Cancer SocietyGoogle Scholar
  2. 2.
    Menendez J, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777PubMedCrossRefGoogle Scholar
  3. 3.
    Kuemmerle N, Rysman E, Lombardo P, Flanagan A, Lipe B, Wells W, Pettus J, Memoli V, Morganelli P, Swinnen J, Timmerman L, Chaychi L, Eisenberg B, Coleman W, Kinlaw W (2011) Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther 10:427–436PubMedCrossRefGoogle Scholar
  4. 4.
    Martel P, Bingham C, McGraw C, Baker C, Morganelli P, Meng M, Jemal A, Moncur J, Kinlaw WB (2005) S14 protein in breast cancer cells: direct evidence for regulation by SREBP-1c, superinduction with progestin, and implication in cell growth. Exp Cell Res 312:278–288PubMedGoogle Scholar
  5. 5.
    Eheman C, Henley J, Ballard-Barbash R, Jacobs E, Schymura M, Noone A, Pan L, Anderson R, Fulton J, Kohler B, Jemal A., Ward E, Plescia M, Ries L, Edwards B (2012) Annual report to the nation on the status of cancer, 1975–2008, featuring cancers associated with excess weight and lack of sufficient activity. Cancer 118:2238–2266Google Scholar
  6. 6.
    Chlebowski R (2012) Obesity and breast cancer: adding to the evidence. J Clin Oncol 30:126–128PubMedCrossRefGoogle Scholar
  7. 7.
    Chlebowski R, Blackburn G, Hoy M, Thomson C, Giuliano A, McAndrew P, Hudis C, Butler J, Shapiro A, Elashoff R (2008), Survival analyses from the women’s intervention nutrition study (WINS) evaluating dietary fat reduction and breast cancer outcome. J. Clin. Oncol. 26(May 20 suppl; abstr 522)Google Scholar
  8. 8.
    Pierce J, Natarajan L, Caan B, Parker B, Greenberg E, Flatt S, Rock C, Kealy S, Al-Delaimy W, Bardwell W, Carlson R, Emond J, Faerber S, Gold E, Hajek R, Hollenbach K, Jones L, Karanja N, Madlensky L, Marshall J, Newman V, Ritenbaugh C, Thomson C, Wasserman L, Stefanick M (2007) Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the women’s healthy eating and living (WHEL) randomized trial. JAMA 298:289–298PubMedCrossRefGoogle Scholar
  9. 9.
    Ip C, Singh M, Thompson H, Scimeca J (1994) Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. Cancer Res 54:1212–1215PubMedGoogle Scholar
  10. 10.
    Ip C, Dong Y, Ip M, Banni S, Carta G, Angioni E, Murru E, Spada S, Melis M, Saebo A (2002) Conjugated linoleic acid isomers and mammary cancer prevention. Nutr Cancer 43:52–58PubMedCrossRefGoogle Scholar
  11. 11.
    Harvatine K, Bauman D (2006) SREBP1 and thyroid hormone responsive spot 14 (S14) are involved in the regulation of bovine mammary lipid synthesis during diet-induced milk fat depression and treatment with CLA. J. Nutr 136:2468–2474PubMedGoogle Scholar
  12. 12.
    Hughes D, Martel P, Kinlaw W, Eisenberg B (2007) The synthetic triterpenoid CDDO-Im inhibits fatty acid synthase expression and has antiproliferative and proapoptotic effects in human liposarcoma cells. Cancer Invest 26:118–127CrossRefGoogle Scholar
  13. 13.
    Donnelly C, Olsen A, Lewis L, Eisenberg B, Eastman A, Kinlaw W (2009) Conjugated linoleic acid (CLA) inhibits expression of the Spot 14 (THRSP) and fatty acid synthase genes and impairs the growth of human breast cancer and liposarcoma cells. Nutr Cancer 61:114–122PubMedCrossRefGoogle Scholar
  14. 14.
    Blankson H, Stakkestad J, Fagertun H, Thom E, Wadstein J, Gudmunsin O (2000) Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr 130:2943–2948PubMedGoogle Scholar
  15. 15.
    Gaullier JM, Halse J, Hoye K, Kristiansen K, Fagertun H, Vik H, Gudmundsen O (2005) Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 135:778–784PubMedGoogle Scholar
  16. 16.
    Brown SB, Maloney M, Kinlaw WB (1997) “Spot 14” protein functions at the pretranslational level in the regulation of hepatic metabolism by thyroid hormone and glucose. J Biol Chem 272:2163–2166PubMedCrossRefGoogle Scholar
  17. 17.
    Moreau A, Teruel C, Beylot M, Albalea V, Tomasi V, Umbdenstock T, Parmentier Y, Sa-Cahuna A, Suc B, Fabre J, Navarro F, Ramos J, Meyer U, Maurel P, Vilarem M, Pascussi J (2009) A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. Hepatology 49:2068–2079PubMedCrossRefGoogle Scholar
  18. 18.
    Kinlaw W, Quinn J, Wells W, Roser-Jones C, Moncur J (2006) S14 in breast cancer: a marker of aggressive disease and a potential therapeutic target. Endocrinology 147:4048–4055PubMedCrossRefGoogle Scholar
  19. 19.
    Wells W, Schwartz G, Morganelli P, Cole B, Chambers J, Kinlaw WB (2006) Expression of “Spot 14” (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker. Breast Cancer Res Treat 98:231–240PubMedCrossRefGoogle Scholar
  20. 20.
    Xu X, Storkson J, Kim S, Sugimoto K, Park Y, Pariza M (2003) Short-term intake of conjugated linoleic acid inhibits lipoprotein lipase and glucose metabolism but does not enhance lipolysis in mouse adipose tissue. J Nutr 133:663–667PubMedGoogle Scholar
  21. 21.
    Kinlaw W, Church J, Harmon J, Mariash C (1995) Direct evidence for a role of the “spot 14” protein in the regulation of lipid synthesis. J Biol Chem 270:16615–16618PubMedCrossRefGoogle Scholar
  22. 22.
    Zhu Q, Anderson G, Mucha G, Parks E, Metkowski J, Mariash C (2005) The Spot 14 protein is required for de novo lipid synthesis in the lactating mammary gland. Endocrinology 146:3343–3350PubMedCrossRefGoogle Scholar
  23. 23.
    Colbert C, Kim C, Moon Y, Henry L, Palnitkar M, McKean W, Fitzgerald K, Deisenhofer J, Horton J, Kwon H (2010) Crystal structure of Spot 14, a modulator of fatty acid synthesis. PNAS 107:18820–18825PubMedCrossRefGoogle Scholar
  24. 24.
    Ip M, Sibel O, Masso-Welch A, Ip C, Meng X, Ou L, Shoemaker S (2007) The t10, c12 isomer of conjugated linoleic acid stimulates mammary tumorigenesis in transgenic mice over-expressing erbB2 in the mammary epithelium. Carcinogenesis 28:1269–1276PubMedCrossRefGoogle Scholar
  25. 25.
    Flowers M, Schroeder J, Borowsky A, Besselsen D, Thomson C, Pandey R, Thompson P (2010) Pilot study on the effects of dietary conjugated linoleic acid on tumorigenesis and gene exprtession in PyMT transgenic mice. Carcinogenesis 31:1642–1649PubMedCrossRefGoogle Scholar
  26. 26.
    Foote M, Giesy S, Bernal-Santos G, Bauman D, Boisclair Y (2010) t10, c12-CLA decreases adiposity in peripubertal mice without dose-related detrimental effects on mammary development, inflammation 3 status and metabolism. Am. J Physiol-Regulatory Intergrative & Comparative Physiol 299:R1521–R1528CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Margit M. McGowan
    • 1
  • Burton L. Eisenberg
    • 2
  • Lionel D. Lewis
    • 3
  • Heather M. Froehlich
    • 4
  • Wendy A. Wells
    • 4
  • Alan Eastman
    • 5
  • Nancy B. Kuemmerle
    • 1
  • Kari M. Rosenkrantz
    • 2
  • Richard J. BarthJr.
    • 2
  • Gary N. Schwartz
    • 1
  • Zhongze Li
    • 6
  • Tor D. Tosteson
    • 7
  • Bernard B. BeaulieuJr.
    • 3
  • William B. Kinlaw
    • 8
  1. 1.Section of Hematology/Oncology, Department of MedicineDartmouth-Hitchcock Medical Center (MM & GS) and White River Junction VA Hospital (NK), and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  2. 2.Section of Surgical Oncology, Department of SurgeryDartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  3. 3.Section of Clinical Pharmacology, Department of MedicineDartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  4. 4.Department of PathologyDartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  5. 5.Dept of PharmacologyThe Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  6. 6.The Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  7. 7.Dept of Family and Community MedicineDartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA
  8. 8.Section of Endocrinology, Department of MedicineDartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, The Geisel School of Medicine at DartmouthLebanonUSA

Personalised recommendations