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The prognostic significance of WWOX expression in patients with breast cancer and its association with the basal-like phenotype

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Abstract

Purpose

The basal-like phenotype has been found to be an independent poor prognostic factor for breast cancer. The aim of this study was to evaluate the association of WW domain-containing oxidoreductase (WWOX) expression with the basal-like subtype and clinicopathological parameters and to determine the prognostic significance of WWOX expression in patients with breast cancer.

Methods

Immunohistochemical analysis of WWOX expression was performed on 267 breast carcinoma samples, and then the mean value of WWOX expression was correlated to the basal-like status and clinicopathological parameters of the samples. The prognostic value of WWOX in primary breast cancer patients was determined for disease-free survival and overall survival.

Results

Expression of WWOX was negative in 29% of cases, and mean WWOX levels were significantly lower in basal-like breast cancers than in those of the non-basal-like subtype (P = 0.01). WWOX negativity was associated with decreased disease-free survival (DFS) (hazard ratio = 1.83; 95% CI, 1.01 to 3.28), but not with overall survival. Other tumor variables that showed a significant association with patient survival times included node status (hazard ratio = 0.38; 95% CI, 0.17 to 0.85) and breast cancer phenotype (hazard ratio = 0.36; 95% CI, 0.19 to 0.68). Multivariate regression analysis showed that lymph node involvement (hazard ratio = 0.43; 95% CI, 0.19 to 0.97) and basal-like subtype (hazard ratio = 0.33; 95% CI, 0.17 to 0.63) were also significant independent prognostic variables, and WWOX expression was of borderline significance for DFS (hazard ratio = 0.56; 95% CI, 0.31 to 1.03).

Conclusions

Reduced WWOX expression is associated with the basal-like subtype and a poor disease-free survival rate for breast cancer patients. Additional studies are warranted to better understand the role of WWOX expression, to further refine prognosis, and to optimize treatment in patients with basal-like breast cancer.

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References

  • Aqeilan RI, Kuroki T, Pekarsky O et al (2004) Loss of WWOX expression in gastric carcinoma. Clin Can Res 10(9):3053–3058

    Article  CAS  Google Scholar 

  • Bednarek AK, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM (2000) WWOX, a novel domain-containing protein mapping to human chromosome 16q23.3–24.1, a region frequently affected in breast cancer. Cancer Res 60(8):2140–2145

    CAS  PubMed  Google Scholar 

  • Bednarek AK, Keck-Waggoner CL, Daniel RL et al (2001) WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res 61(22):8068–8073

    CAS  PubMed  Google Scholar 

  • Cheang MC, Voduc D, Bajdik C et al (2008) Basal-like breast cancer defined by 5 biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14(5):1368–1376

    Article  CAS  PubMed  Google Scholar 

  • Greene FI, Page DI, Fleming ID (2002) AJCC cancer staging manual, 6th edn. Springer, New York

    Book  Google Scholar 

  • Guler G, Ulner A, Guler N et al (2004) The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Cancer 100(8):1605–1614

    Article  CAS  PubMed  Google Scholar 

  • Guler G, Iliopoulos D, Guler N, Himmetoglu C, Hayran M, Huebner K (2007) WWOX and Ap2r expression levels predict tamoxifen response. Clin Cancer Res 13:6115–6121

    Article  CAS  PubMed  Google Scholar 

  • Haffty BG, Yang Q, Reiss M et al (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657

    Article  PubMed  Google Scholar 

  • Iliopoulos D, Guler G, Han SH-Y et al (2005) Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Oncogene 24(9):1625–1633

    Article  CAS  PubMed  Google Scholar 

  • Iliopoulos D, Fabbri M, Druck T, Qin HR, Han SY, Huebner K (2007) Inhibition of breast cancer cell growth in vitro and in vivo: effect of restoration of WWOX expression. Clin Cancer Res 13(1):268–274

    Article  CAS  PubMed  Google Scholar 

  • Jimenez RE, Wallis T, Visscher DW (2001) Centrally necrotizing carcinomas of the breast: a distinct histologic subtype with aggressive clinical behavior. Am J Surg Pathol 25(3):331–337

    Article  CAS  PubMed  Google Scholar 

  • Kreike B, van Kouwenhove M, Horlings H et al (2007) Gene expression profiling and histopathological characterization of triple negative/basal-like breast carcinomas. Breast Cancer Res 9(5):R65

    Article  PubMed  Google Scholar 

  • Kuroki T, Trapasso F, Shiraishi T et al (2002) Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. Cancer Res 62(8):2258–2260

    CAS  PubMed  Google Scholar 

  • Kuroki T, Yendamuri S, Trapasso F et al (2004) The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin Cancer Res 10(7):2459–2465

    Article  CAS  PubMed  Google Scholar 

  • Le Doussal V, Tubiana-Hulin M, Friedman S, Hacene K, Spyratos F, Brunet M (1989) Prognostic value of histologic grade nuclear components of Scarff-Bloom-Richardson (SBR): an improved score modification based on a multivariate analysis of 1262 invasive ductal breast carcinomas. Cancer 64(9):1914–1921

    Article  CAS  PubMed  Google Scholar 

  • Livasy CA, Karaca G, Nanda R et al (2006) Phenotype evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 19(2):264–271

    Article  CAS  PubMed  Google Scholar 

  • Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374

    Article  CAS  PubMed  Google Scholar 

  • Nunez MI, Rosen DG, Ludes-Meyers JH et al (2005a) WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome. BMC Cancer 5(1):64

    Article  PubMed  Google Scholar 

  • Nunez MI, Ludes-Meyers J, Abba MC et al (2005b) Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status. Breast Cancer Res Treat 89(2):99–105

    Article  PubMed  Google Scholar 

  • Paige AJ, Taylor KJ, Taylor C et al (2001) WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci 98(20):11417–11422

    Article  CAS  PubMed  Google Scholar 

  • Parikh RR, Housman D, Qifeng Y, Toppmeyer D, Wilson LD, Haffty BG (2008a) Prognostic value of triple-negative phenotype at the time of locally recurrent, conservatively treated breast cancer. Int J Radiat Oncol Biol Phys 72(4):1–8

    Google Scholar 

  • Parikh RR, Yang Q, Higgins SA, Haffty BG (2008b) Outcomes in young women with breast cancer of triple-negative phenotype: the prognostic significance of CK19 expression. Int J Radiat Oncol Biol Phys 70(1):35–42

    Article  PubMed  Google Scholar 

  • Park SW, Ludes-Meyers J, Zimonjic DB, Durkin ME, Popescu NC, Aldaz CM (2004) Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma. Br J Cancer 91(4):753–759

    CAS  PubMed  Google Scholar 

  • Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    Article  CAS  PubMed  Google Scholar 

  • Purohit A, Newman SP, Reed MJ (2002) The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 4(2):65–69

    Article  CAS  PubMed  Google Scholar 

  • Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423

    Article  CAS  PubMed  Google Scholar 

  • Tuck AB, O’Malley FP, Singhal H et al (1997) Osteopontin and p53 expression are associated with tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas. Arch Pathol Lab Med 121(6):578–584

    CAS  PubMed  Google Scholar 

  • Turner BC, Gumbs AA, Carter D, Glazer PM, Haffty BG (2004) Cyclin D1 expression and early breast cancer recurrence following lumpectomy and radiation. Int J Radiat Oncol Biol Phys 47(5):1169–1176

    Google Scholar 

  • Wang X, Chao L, Ma G et al (2008) Increased expression of osteopontin in patients with triple-negative breast cancer. Eur J Clin Invest 38(6):438–446

    Article  CAS  PubMed  Google Scholar 

  • Yendamuri S, Kuroki T, Trapasso F et al (2003) WW Domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. Cancer Res 63(4):878–881

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work supported, in whole or in part, by grants from Shandong Province Natural Science Foundation (No. Y2006C30), Shandong Health and Medicine Founds, China Postdoctoral Foundation (No.20090461225, 20090461226), Doctor Funds of Shandong Province (No. BS2009SW031), and Science and Technology Development Plan of Jinan, China (No. 061033-2).

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Authors and Affiliations

  1. Department of Surgery, Shandong University School of Medicine, Jinan, 250012, China

    Xiao Wang, Guohui Ma, Liansheng Chen, Yixiu Zang & Jingzhong Sun

  2. Qilu Hospital of Shandong University, Jinan, 250012, China

    Lan Chao

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  1. Xiao Wang
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  2. Lan Chao
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  3. Guohui Ma
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  4. Liansheng Chen
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  5. Yixiu Zang
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  6. Jingzhong Sun
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Correspondence to Xiao Wang.

Additional information

X. Wang and L. Chao contributed equally to this work.

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Wang, X., Chao, L., Ma, G. et al. The prognostic significance of WWOX expression in patients with breast cancer and its association with the basal-like phenotype. J Cancer Res Clin Oncol 137, 271–278 (2011). https://doi.org/10.1007/s00432-010-0880-1

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  • DOI: https://doi.org/10.1007/s00432-010-0880-1

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