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Fatty acid binding protein 7 expression and its sub-cellular localization in breast cancer

  • Preclinical Study
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Abstract

FABP7 is a member of the multi-gene fatty acid binding protein family. It is expressed in the mammary gland and has been shown to function as inhibitor of proliferation of breast tumour cells and to promote differentiation through the JAK/Stat pathway. Cytoplasmic FABP7 expression has been shown to be associated with a favourable prognosis of basal-like breast cancer. In other tissues, varying sub-cellular localization of FABP7 between the nucleus and cytoplasm has been observed. Tissue microarray preparations of well-characterized series of 1,249 unselected and 245 ER-negative invasive breast cancers with a long-term follow-up were investigated in this study to assess the biological and clinical significance of FABP7 sub-cellular localization using immunohistochemistry. Both nuclear and cytoplasmic FABP7 were observed. Nuclear FABP7 was associated with high histologic grade, mitotic frequency, pleomorphism and stage, in addition to basal phenotype (BP) and triple-negative (TN) phenotype. Nuclear FABP7 expression showed an association with expression of markers associated with proliferation and cell-cycle control including Ki67, p53 and p21; however, cytoplasmic FABP7 was associated only with Ki67 and P53 (P = 0.001, < 0.001 respectively). Interestingly, in multivariate analysis, nuclear FABP7 expression in BP was significantly associated with longer DFI (P = 0.025) independent of cytoplasmic expression. Tumours with only nuclear positive FABP7 expression had significantly better prognosis than those with only cytoplasmic expression. This is the first study elucidating the sub-cellular localization of FABP7 in a large series of breast cancer cases. Our observations demonstrate the considerable heterogeneity in expression patterns of FABP7 within breast cancer that relates to differences in biological behaviour especially in basal-like breast cancer. Further investigation of the biology of FABP7 in breast cancer is warranted.

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Abbreviations

BCSS:

Breast cancer specific survival

BLBC:

Basal-like breast cancer

BP:

Basal phenotype

CaKi-2:

Human kidney clear cell carcinoma cell line

CISH:

Chromogenic in situ hybridisation

CK5:

Cytokeratin5

CK14:

Cytokeratin14

CK17:

Cytokeratin17

DFI:

Disease-free interval

EGFR:

Epidermal growth factor receptor 1

ER:

Estrogen

FABP7:

Fatty acid binding protein 7

FAS:

Fatty acid synthase

HER2:

Human epidermal growth factor receptor 2

IHC:

Immunohistochemistry

JAK/STAT:

Janus kinase/signal transducer and activator of transcription

LBP:

Lipid-binding protein

MIB1:

Mindbomb homolog 1

NST:

No special type

PPAR:

Peroxisome proliferator-activated receptor

PgR:

Progesterone

TMA:

Tissue micro array

PIAS γ:

Protein inhibitor of activated STAT protein γ

References

  1. Xu LZ, Sánchez R, Sali A, Heintz N (1996) Ligand specificity of brain lipid-binding protein. J Biol Chem 271(40):24711–24719

    Article  PubMed  CAS  Google Scholar 

  2. Wolfrum C, Borrmann CM, Borchers T, Spener F (2001) Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha—and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci USA 98(5):2323–2328. doi:10.1073/pnas.051619898051619898

    Article  PubMed  CAS  Google Scholar 

  3. Huang H, Starodub O, McIntosh A, Kier AB, Schroeder F (2002) Liver fatty acid-binding protein targets fatty acids to the nucleus. J Biol Chem 277(32):29139

    Article  PubMed  CAS  Google Scholar 

  4. Feng L, Heintz N (1995) Differentiating neurons activate transcription of the brain lipid-binding protein gene in radial glia through a novel regulatory element. Development 121(6):1719–1730

    PubMed  CAS  Google Scholar 

  5. Shimizu F, Watanabe TK, Shinomiya H, Nakamura Y, Fujiwara T (1997) Isolation and expression of a cDNA for human brain fatty acid-binding protein (B-FABP). Biochim Biophys Acta 1354(1):24–28. doi:S0167-4781(97)00115-2

    Article  PubMed  CAS  Google Scholar 

  6. Godbout R, Bisgrove DA, Shkolny D, Day RS 3rd (1998) Correlation of B-FABP and GFAP expression in malignant glioma. Oncogene 16(15):1955–1962. doi:10.1038/sj.onc.1201740

    Article  PubMed  CAS  Google Scholar 

  7. Kaloshi G, Mokhtari K, Carpentier C, Taillibert S, Lejeune J, Marie Y, Delattre JY, Godbout R, Sanson M (2007) FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status. J Neurooncol 84(3):245–248

    Article  PubMed  Google Scholar 

  8. Mita R, Beaulieu MJ, Field C, Godbout R (2010) Brain fatty acid-binding protein and omega-3/omega-6 fatty acids: mechanistic insight into malignant glioma cell migration. J Biol Chem 285(47):37005–37015. doi:10.1074/jbc.M110.170076

    Article  PubMed  CAS  Google Scholar 

  9. Haunerland NH, Spener F (2004) Fatty acid-binding proteins–insights from genetic manipulations. Prog Lipid Res 43(4):328–349. doi:10.1016/j.plipres.2004.05.001S016378270400013X

    Article  PubMed  CAS  Google Scholar 

  10. Wang M, Liu YE, Ni J, Aygun B, Goldberg ID, Shi YE (2000) Induction of mammary differentiation by mammary-derived growth inhibitor-related gene that interacts with an omega-3 fatty acid on growth inhibition of breast cancer cells. Cancer Res 60(22):6482–6487

    PubMed  CAS  Google Scholar 

  11. Shi YE, Ni J, Xiao G, Liu YE, Fuchs A, Yu G, Su J, Cosgrove JM, Xing L, Zhang M (1997) Antitumor activity of the novel human breast cancer growth inhibitor, mammary-derived growth inhibitor-related gene, MRG. Cancer Res 57(15):3084

    PubMed  CAS  Google Scholar 

  12. Tölle A, Krause H, Miller K, Jung K, Stephan C (2011) Importance of brain–type fatty acid binding protein for cell-biological processes in human renal carcinoma cells. Oncol Rep 25(5):1307–1312

    Article  PubMed  Google Scholar 

  13. Takaoka N, Takayama T, Teratani T, Sugiyama T, Mugiya S, Ozono S (2011) Analysis of the regulation of fatty acid binding protein 7 expression in human renal carcinoma cell lines. BMC Mol Biol 12:31. doi:10.1186/1471-2199-12-31

    Article  PubMed  CAS  Google Scholar 

  14. Glatz JFC, Luiken JJFP, van Bilsen M, van der Vusse GJ (2002) Cellular lipid binding proteins as facilitators and regulators of lipid metabolism. Mol Cell Biochem 239(1):3–7

    Article  PubMed  CAS  Google Scholar 

  15. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, Mackay A, Grigoriadis A, Tutt A, Ashworth A, Reis-Filho JS, Smalley MJ (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3):403–417

    Article  PubMed  CAS  Google Scholar 

  16. Zhang H, Rakha EA, Ball GR, Spiteri I, Aleskandarany M, Paish EC, Powe DG, Macmillan RD, Caldas C, Ellis IO, Green AR (2010) The proteins FABP7 and OATP2 are associated with the basal phenotype and patient outcome in human breast cancer. Breast Cancer Res Treat 121(1):41–51. doi:10.1007/s10549-009-0450-x

    Article  PubMed  CAS  Google Scholar 

  17. Madjd Z, Pinder SE, Paish C, Ellis IO, Carmichael J, Durrant LG (2003) Loss of CD59 expression in breast tumours correlates with poor survival. J Pathol 200(5):633–639. doi:10.1002/path.1357

    Article  PubMed  CAS  Google Scholar 

  18. Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26(15):2568–2581

    Article  PubMed  Google Scholar 

  19. García-Caballero T, Grabau D, Green AR, Gregory J, Schad A, Kohlwes E, Ellis IO, Watts S, Mollerup J (2010) Determination of HER2 amplification in primary breast cancer using dual-colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens. Histopathology 56:472–480

    Article  PubMed  Google Scholar 

  20. Aleskandarany MA, Green AR, Benhasouna AA, Barros FF, Neal KR, Reis-Filho JS, Ellis IO, Rakha EA (2011) Prognostic value of proliferation assay in the luminal, HER2 positive and triple negative biological classes of breast cancer. Breast Cancer Res 14(1):R3

    Article  Google Scholar 

  21. Rimm DL, Camp RL, Charette LA, Olsen DA, Provost E (2001) Amplification of tissue by construction of tissue microarrays. Exp Mol Pathol 70(3):255–264

    Article  PubMed  CAS  Google Scholar 

  22. Callagy G, Cattaneo E, Daigo Y, Happerfield L, Bobrow LG, Pharoah PDP, Caldas C (2003) Molecular classification of breast carcinomas using tissue microarrays. Diagn Mol Pathol 12(1):27

    Article  PubMed  CAS  Google Scholar 

  23. Ginestier C, Charafe-Jauffret E, Bertucci F, Eisinger F, Geneix J, Bechlian D, Conte N, Adélaïde J, Toiron Y, Nguyen C, Viens P, Mozziconacci MJ, Houlgatte R, Birnbaum D, Jacquemier J (2002) Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast tumor markers. Am J Pathol 161(4):1223–1233

    Article  PubMed  CAS  Google Scholar 

  24. Feng L, Hatten ME, Heintz N (1994) Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron 12(4):895–908

    Article  PubMed  CAS  Google Scholar 

  25. Liang Y, Bollen AW, Aldape KD, Gupta N (2006) Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma. BMC Cancer 6:97. doi:10.1186/1471-2407-6-97

    Article  PubMed  Google Scholar 

  26. Goto Y, Koyanagi K, Narita N, Kawakami Y, Takata M, Uchiyama A, Nguyen L, Nguyen T, Ye X, Morton DL (2009) Aberrant fatty acid-binding protein-7 gene expression in cutaneous malignant melanoma. J Invest Dermatol 130(1):221–229

    Article  Google Scholar 

  27. Yang Y, Morin PJ, Han WF, Chen T, Bornman DM, Gabrielson EW, Pizer ES (2003) Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res 282(2):132–137

    Article  PubMed  CAS  Google Scholar 

  28. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.19136709898/19/10869

    Article  PubMed  CAS  Google Scholar 

  29. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  PubMed  CAS  Google Scholar 

  30. Rakha EA, El-Rehim DA, Paish C, Green AR, Lee AH, Robertson JF, Blamey RW, Macmillan D, Ellis IO (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42(18):3149–3156. doi:10.1016/j.ejca.2006.08.015

    Article  PubMed  CAS  Google Scholar 

  31. Fulford LG, Reis-Filho JS, Ryder K, Jones C, Gillett CE, Hanby A, Easton D, Lakhani SR (2007) Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res 9(1):R4. doi:10.1186/bcr1636

    Article  PubMed  Google Scholar 

  32. Tang XY, Umemura S, Tsukamoto H, Kumaki N, Tokuda Y, Osamura RY (2010) Overexpression of fatty acid binding protein-7 correlates with basal-like subtype of breast cancer. Pathol Res Pract 206(2):98–101. doi:10.1016/j.prp.2009.06.010

    Article  PubMed  CAS  Google Scholar 

  33. Aksglaede L, Wikstrom AM, Rajpert-De Meyts E, Dunkel L, Skakkebaek NE, Juul A (2006) Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 12(1):39–48. doi:10.1093/humupd/dmi039

    Article  PubMed  Google Scholar 

  34. Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP, Ye X, Liu B, Elashoff D, Hoon DS, Walter MA, Martens JW, Richardson AL, Giuliano AE, Cui X (2010) FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 70(10):3870–3876. doi:10.1158/0008-5472.CAN-09-4120

    Article  PubMed  CAS  Google Scholar 

  35. Liang Y, Bollen AW, Nicholas MK, Gupta N (2005) Id4 and FABP7 are preferentially expressed in cells with astrocytic features in oligodendrogliomas and oligoastrocytomas. BMC Clin Pathol 5:6. doi:10.1186/1472-6890-5-6

    Article  PubMed  Google Scholar 

  36. Solomayer EF, Diel I, Meyberg G, Gollan C, Bastert G (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59(3):271–278

    Article  PubMed  CAS  Google Scholar 

  37. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602

    Article  PubMed  CAS  Google Scholar 

  38. Niwińska A, Murawska M, Pogoda K (2010) Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT). Ann Oncol 21(5):942–948

    Article  PubMed  Google Scholar 

  39. Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT (2006) Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. The American journal of surgical pathology 30(9):1097

    Article  PubMed  Google Scholar 

  40. Klein A, Olendrowitz C, Schmutzler R, Hampl J, Schlag PM, Maass N, Arnold N, Wessel R, Ramser J, Meindl A (2009) Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett 276(2):212–220

    Article  PubMed  CAS  Google Scholar 

  41. Goto Y, Matsuzaki Y, Kurihara S, Shimizu A, Okada T, Yamamoto K, Murata H, Takata M, Aburatani H, Hoon DSB (2006) A new melanoma antigen fatty acid-binding protein 7, involved in proliferation and invasion, is a potential target for immunotherapy and molecular target therapy. Cancer Res 66(8):4443

    Article  PubMed  CAS  Google Scholar 

  42. Michalik L, Desvergne B, Wahli W (2004) Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer 4(1):61–70. doi:10.1038/nrc1254nrc1254

    Article  PubMed  CAS  Google Scholar 

  43. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci USA 95(18):10626–10631

    Article  PubMed  CAS  Google Scholar 

  44. Slipicevic A, Jørgensen K, Skrede M, Rosnes AK, Trøen G, Davidson B, Flørenes VA (2008) The fatty acid binding protein 7 (FABP7) is involved in proliferation and invasion of melanoma cells. BMC Cancer 8(1):276

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Histopathology and School of Molecular Medical Sciences, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK

    Alaa T. Alshareeda, Emad A. Rakha, Christopher C. Nolan, Ian O. Ellis & Andrew R. Green

  2. Breast Cancer Pathology Research Group, School of Molecular Medical Sciences, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

    Andrew R. Green

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  1. Alaa T. Alshareeda
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Correspondence to Alaa T. Alshareeda.

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Alshareeda, A.T., Rakha, E.A., Nolan, C.C. et al. Fatty acid binding protein 7 expression and its sub-cellular localization in breast cancer. Breast Cancer Res Treat 134, 519–529 (2012). https://doi.org/10.1007/s10549-012-2083-8

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  • DOI: https://doi.org/10.1007/s10549-012-2083-8

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