Breast Cancer Research and Treatment

, Volume 98, Issue 2, pp 231–240 | Cite as

Expression of “Spot 14” (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker

  • Wendy A. Wells
  • Gary N. Schwartz
  • Peter M. Morganelli
  • Bernard F. Cole
  • Jennifer J. Gibson
  • William B. Kinlaw
Preclinical study


Most breast cancers are “lipogenic”, defined by high fatty acid synthase (FAS) content and dependence on fatty acid synthesis for growth and survival. S14 (Spot 14; THRSP) is a nuclear protein that activates genes required for fatty acid synthesis. The S14 gene is amplified in ~15% of breast cancers, but clinical correlates of its expression were unknown. We analyzed 131 breast cancers by immunohistochemistry for S14 and FAS. Staining was graded 0, 1, or 2+, and scores were correlated with traditional tumor markers, histological features, and outcome. S14 and FAS staining were related to tumor size (p=0.05 for S14, p=0.038 for FAS), but not to stage. S14 but not FAS scores correlated with tumor grade in both DCIS (p=0.003) and invasive cases (p<0.001). Invasive cases (pooled node − and +) with weak S14 staining (n=21) showed no recurrence over 3000 d follow-up, including 10 cases with lymph node involvement, whereas 32% of 67 strongly-staining tumors recurred (log rank p<0.0001). S14 scores did not cosegregate with sex steroid receptors, Her2/neu, or cyclin D1. Low level S14 expression is associated with prolonged disease-free survival in invasive cases, including those with nodal metastasis. High-level expression of S14 identifies a subset of high-risk breast cancers that is not specified by analysis of sex steroid receptors, Her2/neu, or cyclin D1, and provides a molecular correlate to histologic features that predict recurrence.


chromosome 11q13 gene amplification lipogenesis tumor markers 



ductal carcinoma in situ


estrogen receptor


fatty acid synthase


fluorescent in situ hybridization


polymerase chain reaction


progesterone receptor


spot 14


thyroid hormone-responsive spot 14 protein


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We thank Dr. Vincent Memoli for consultation regarding immunohistochemistry, Ms. Maudine Waterman for performing the immunostaining, and Drs. Murray Korc and Mark Schneider for critical readings of the manuscript.

Grant support. NIH RO1 DK 058961 (to W.B.K.), and U.S. Department of Defense grant DAMD17–03-1-0544 (to W.B.K.).


  1. 1.
    Cunningham B, Moncur J, Huntington J, Kinlaw WB “Spot 14” protein: a metabolic integrator in normal and neoplastic cells Thyroid 8: 815–825, 1998PubMedCrossRefGoogle Scholar
  2. 2.
    Kinlaw W, Church J, Harmon J, Mariash C Direct evidence for a role of the “spot 14” protein in the regulation of lipid synthesis J Biol Chem 270: 16615–16618, 1995CrossRefPubMedGoogle Scholar
  3. 3.
    Brown SB, Maloney M, Kinlaw WB “Spot 14” protein functions at the pretranslational level in the regulation of hepatic metabolism by thyroid hormone and glucose J Biol Chem 272: 2163–2166, 1997CrossRefPubMedGoogle Scholar
  4. 4.
    Zhu Q, Anderson G, Mucha G, Parks E, Metkowski J, Mariash C The spot 14 protein is required for de novo lipid synthesis in the lactating mammary gland Endocrinol 146: 3343–3350, 2005CrossRefGoogle Scholar
  5. 5.
    Moncur J, Park J, Mohandes TK, Memoli V, Kinlaw W The “spot 14” gene resides on the telomeric end of the 11q13 amplicon and is expressed in lipogenic breast cancers Proc Natl Acad Sci USA 95: 6989–6994, 1998CrossRefPubMedGoogle Scholar
  6. 6.
    Kuhajda F, Piantadosi S, Pasternack G Haptoglobin-related protein (Hpr) epitopes in breast cancer as a predictor of recurrence of the disease NEJM 321: 636–641, 1989PubMedGoogle Scholar
  7. 7.
    Kuhajda F Fatty-acid synthase and human cancer: New perspectives on its role in tumor biology Nutrition 16: 202–208, 2000CrossRefPubMedGoogle Scholar
  8. 8.
    Pizer E, Wood F, Heine H, Romanstev F, Pasternak G, Kuhajda F Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer Cancer Res 56: 1189–1193, 1996PubMedGoogle Scholar
  9. 9.
    Pizer E, Jackisch C, Wood F, Pasternak G, Davidson N, Kuhajda F Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells Cancer Res 56: 2745–2747, 1996PubMedGoogle Scholar
  10. 10.
    Kridel S, Axelrod F, Rozenkrantz N, Smith J Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity Cancer Res 64: 2070–2075, 2004CrossRefPubMedGoogle Scholar
  11. 11.
    Hinds P, Dowdy S, Eaton E, Arnold A, Weinberg R Function of a human cyclin gene as an oncogene Proc Natl Acad Sci USA 91: 709–713, 1994PubMedCrossRefGoogle Scholar
  12. 12.
    Petty W, Dragnev K, Memoli V, et al. Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers Clin Canc Res 10: 7547–7554, 2004CrossRefGoogle Scholar
  13. 13.
    Martel P, Bingham C, McGraw C, Baer C, Morganelli P, Meng M, Armstrong J, Moncur J, Kinlaw W S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and implication on cell growth Exp Cell Res 312: 278–288, 2006PubMedGoogle Scholar
  14. 14.
    Kinlaw WB, Ling NC, Oppenheimer JH Identification of rat S14 protein and comparison of its regulation with that of mRNA S14 employing synthetic peptide antisera J Biol Chem 264: 19779–19783, 1989PubMedGoogle Scholar
  15. 15.
    Jensen V, Ladekarl M, Holm-Nielsen P, Melsen F, Soerensen F The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer J Pathol 176: 343–352, 1995CrossRefPubMedGoogle Scholar
  16. 16.
    Milgraum L, Witters L, Pasternack G, Kuhajda F Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma Clin Canc Res 3: 2115–2120, 1997Google Scholar
  17. 17.
    Menard S, Pupa S, Campiglio M, Tagliabue E Biologic and therapeutic role of Her2 in cancer Oncogene 22: 6570–6578, 2003CrossRefPubMedGoogle Scholar
  18. 18.
    Schuuring E, Verhoeven E, van Tintern H, et al. Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer Cancer Res 52: 5229–5234, 1992PubMedGoogle Scholar
  19. 19.
    Champeme M, Bieche I, Lizard S, Lidereau R 11q13 amplification in local recurrence of human primary breast cancer Genes, Chromosome Cancer 12: 128–133, 1995CrossRefGoogle Scholar
  20. 20.
    Alo P, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients Cancer 77: 474–482, 1995CrossRefGoogle Scholar
  21. 21.
    Sanchez-Rodriguez J, Kanininda-Tshilumbu J, Santos A, Perez-Castillo A The spot 14 protein inhibits growth and induces differentiation and cell death of human MCF-7 breast cancer cells Biochem J 392(Pt 1): 57–65, 2005CrossRefPubMedGoogle Scholar
  22. 22.
    Heemers H, Vanderhoydonc F, Heyns W, Verhoeven G, Swinnen J Progestins and androgens increase expression of spot 14 in T47-D breast tumor cells Biochem Biophys Res Commun 269: 209–212, 2000CrossRefPubMedGoogle Scholar
  23. 23.
    Kumar-Sinha C, Ignatoski K, Lippman M, Ethier S, Chinnaiyan A Transcriptome analysis of Her2 reveals a molecular connection to fatty acid synthesis Cancer Res 63: 132–139, 2003PubMedGoogle Scholar
  24. 24.
    Moncur J, Park J, Maloney M, Mohandas TK, Kinlaw WB Assignment of the human “spot 14’ gene to 11q13.5 by fluorescence in situ hybridization Cytogen Cell Genet 78: 131–132, 1997CrossRefGoogle Scholar
  25. 25.
    Dickson C, Fantl V, Gillett C, et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer Cancer Lett 90: 43–50, 1995CrossRefPubMedGoogle Scholar
  26. 26.
    Gillet C, Fantl V, Bartek J, Dickson C, Barnes D, Peters G Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining Cancer Res 54: 1812–1817, 1994PubMedGoogle Scholar
  27. 27.
    Al-Kuraya K, Schrami P, Torhorst J, Tapia C, Sauter G Prognostic relevance of gene amplifications and coamplifications in breast cancer Cancer Res 64: 8534–8540, 2004CrossRefPubMedGoogle Scholar
  28. 28.
    Courjal F, Cuny M, Simony-Lafontaine J, et al. Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups Cancer Res 57: 4360–4365, 1997PubMedGoogle Scholar
  29. 29.
    Michalides R, Hageman P, van Tintern H, et al. A clincopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer British J Cancer 73: 728–734, 1996Google Scholar
  30. 30.
    Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G Cyclin D1 and prognosis in human breast cancer Int J Cancer 69: 92–99, 1996CrossRefPubMedGoogle Scholar
  31. 31.
    Seshadri R, Lee C, Hui R, McCaul K, Horsfall D, Sutherland R Cyclin D1 amplification is not associated with reduced overall survival in primary breast cancer but may predict early relapse in patients with features of good prognosis Clin Cancer Res 2: 1177–1844, 1996PubMedGoogle Scholar
  32. 32.
    Chlebowski R, Blackburn G, Elashoff R, et al. Dietary fat reduction in postmenopausal women with primary breast cancer: Phase III Women’s Interventioon Nutrition Study (WINS) Proc Am Soc Clin Oncol 23:3s, 2005Google Scholar
  33. 33.
    Weiss L, Hoffman G, Schreiber R, et al. Fatty-Acid Biosynthesis in Man, a Pathway of Minor Importance J Biol Chem 367: 905–912, 1986Google Scholar
  34. 34.
    Perou C, Jeffrey S, van de Rijn M, et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers Proc Natl Acad Sci USA 96: 9212–9217, 1999CrossRefPubMedGoogle Scholar
  35. 35.
    Desai K, Xiao N, Wang W, et al. Initiating oncogenic event determines gene expression patterns of human breast cancer models.Proc Natl Acad Sci USA 99: 6967–6972, 2002CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Wendy A. Wells
    • 1
    • 2
  • Gary N. Schwartz
    • 2
    • 3
  • Peter M. Morganelli
    • 2
    • 4
  • Bernard F. Cole
    • 2
    • 5
  • Jennifer J. Gibson
    • 2
    • 5
  • William B. Kinlaw
    • 2
    • 3
    • 6
  1. 1.Department of PathologyDartmouth Medical SchoolLebanonUSA
  2. 2.Norris Cotton Cancer CenterDartmouth Medical SchoolLebanonUSA
  3. 3.Department of MedicineDartmouth Medical SchoolLebanonUSA
  4. 4.US Department of Veterans AffairsVA HospitalWhite River Jct.USA
  5. 5.Department of Community and Family MedicineDartmouth Medical SchoolLebanonUSA
  6. 6.Department of Pathology, Division of endocrinology and metabolismDartmouth Medical SchoolLebanonUSA

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