J Breast Cancer.  2017 Dec;20(4):361-367. 10.4048/jbc.2017.20.4.361.

Wnt7a Deficiency Could Predict Worse Disease-Free and Overall Survival in Estrogen Receptor-Positive Breast Cancer

• Yi K
• Min KW
• Wi YC
• Kim Y
• Shin SJ
• Chung MS
• Jang K
• Paik SS

• KMID: 2398206
• DOI: http://doi.org/10.4048/jbc.2017.20.4.361

Abstract

PURPOSE
Wnt7a is a glycoprotein involved in embryonic development and the progression of different types of malignant tumors. This study aimed to detect the level of Wnt7a expression in breast cancer and explore its role in the disease progression and prognosis.
METHODS
A total of 258 patients diagnosed with invasive ductal carcinoma of the breast were included in this study. Using tissue microarray and immunohistochemical staining, we evaluated the association between Wnt7a expression and clinicopathological parameters, and the prognostic value of Wnt7a.
RESULTS
Wnt7a expression was significantly correlated with estrogen receptor (ER) expression (odds ratio, 3.95; 95% confidence interval [CI], 1.99-7.80; p < 0.001). On univariate and multivariate analyses, loss of Wnt7a expression was associated with poor disease-free survival (DFS) (multivariate hazard ratio [HR], 9.12; 95% CI, 1.80-46.09; p=0.008), but not with poor overall survival (OS). In the ER-positive group (n=114), loss of Wnt7a expression was an independent prognostic factor for shorter DFS (multivariate HR, 13.54; 95% CI, 1.11-165.73; p=0.042) and OS (multivariate HR, 4.76; 95% CI, 1.29-17.61; p=0.019) on univariate and multivariate analyses. However, in the ER-negative group, there was no significant difference in DFS and OS according to Wnt7a expression.
CONCLUSION
The loss of Wnt7a expression might be a meaningful factor in assessing DFS and OS, especially in ER-positive breast cancer.

Keyword

Breast neoplasms; Estrogen receptors; Prognosis; Wnt proteins

MeSH Terms

Breast Neoplasms*
Breast*
Carcinoma, Ductal
Disease Progression
Disease-Free Survival
Embryonic Development
Estrogens*
Female
Glycoproteins
Humans
Multivariate Analysis
Pregnancy
Prognosis
Receptors, Estrogen
Wnt Proteins
Estrogens
Glycoproteins
Receptors, Estrogen
Wnt Proteins

Figure

• 

  Figure 1 Representative photographs of Wnt7a expression in the cytoplasm of neoplastic cells. (A) Negative, (B) positive (immunohistochemical stain for Wnt7a, original magnification ×200).

• 

  Figure 2 Expression of Wnt7a according to molecular subtype. Wnt7a negativity is frequently observed in the triple-negative group compared with other groups including luminal A, luminal B human epidermal growth factor receptor 2 (HER2)−, luminal B HER2+, and HER2 (p<0.001). Values in parentheses represent percentage.

• 

  Figure 3 Patients' survival according to Wnt7a expression. Kaplan-Meier curves representing disease-free survival in all cases (A), the estrogen receptor (ER)-positive group (B) and the progesterone receptor (PR)-positive group (C) and overall survival in all cases (D), the ER-positive group (E) and the PR-positive group (F).

Reference

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61:69–90. PMID: 21296855.

2. Dixon JM, Page DL, Anderson TJ, Lee D, Elton RA, Stewart HJ, et al. Long-term survivors after breast cancer. Br J Surg. 1985; 72:445–448. PMID: 4016513.

3. Jezierska A, Motyl T. Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit. 2009; 15:RA32–RA40. PMID: 19182722.

4. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, et al. Strategies for subtypes: dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011; 22:1736–1747. PMID: 21709140.

5. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004; 20:781–810. PMID: 15473860.

6. Kirikoshi H, Katoh M. Expression of WNT7A in human normal tissues and cancer, and regulation of WNT7A and WNT7B in human cancer. Int J Oncol. 2002; 21:895–900. PMID: 12239632.

7. Avgustinova A, Iravani M, Robertson D, Fearns A, Gao Q, Klingbeil P, et al. Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat Commun. 2016; 7:10305. PMID: 26777421.

8. Liu Y, Meng F, Xu Y, Yang S, Xiao M, Chen X, et al. Overexpression of Wnt7a is associated with tumor progression and unfavorable prognosis in endometrial cancer. Int J Gynecol Cancer. 2013; 23:304–311. PMID: 23321718.

9. Zhang XL, Peng CJ, Peng J, Jiang LY, Ning XM, Zheng JH. Prognostic role of Wnt7a expression in ovarian carcinoma patients. Neoplasma. 2010; 57:545–551. PMID: 20845993.

10. Ramos-Solano M, Meza-Canales ID, Torres-Reyes LA, Alvarez-Zavala M, Alvarado-Ruíz L, Rincon-Orozco B, et al. Expression of WNT genes in cervical cancer-derived cells: implication of WNT7A in cell proliferation and migration. Exp Cell Res. 2015; 335:39–50. PMID: 25978974.

11. Bikkavilli RK, Avasarala S, Van Scoyk M, Arcaroli J, Brzezinski C, Zhang W, et al. Wnt7a is a novel inducer of beta-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene. 2015; 34:5317–5328. PMID: 25728679.

12. Ochoa-Hernández AB, Ramos-Solano M, Meza-Canales ID, García-Castro B, Rosales-Reynoso MA, Rosales-Aviña JA, et al. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation. BMC Cancer. 2012; 12:60. PMID: 22313908.

13. Kondratov AG, Kvasha SM, Stoliar LA, Romanenko AM, Zgonnyk YM, Gordiyuk VV, et al. Alterations of the WNT7A gene in clear cell renal cell carcinomas. PLoS One. 2012; 7:e47012. PMID: 23056560.

14. Hirata T, Zheng Q, Chen Z, Kinoshita H, Okamoto J, Kratz J, et al. Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma. Oncol Rep. 2015; 33:2052–2060. PMID: 25632963.

15. Peng C, Zhang X, Wang Y, Li L, Wang Q, Zheng J. Expression and prognostic significance of Wnt7a in human endometrial carcinoma. Obstet Gynecol Int. 2012; 2012:134962. PMID: 23304155.

16. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987; 8:138–140. PMID: 3303008.

17. Ohira T, Gemmill RM, Ferguson K, Kusy S, Roche J, Brambilla E, et al. WNT7a induces E-cadherin in lung cancer cells. Proc Natl Acad Sci U S A. 2003; 100:10429–10434. PMID: 12937339.

18. Yoshioka S, King ML, Ran S, Okuda H, MacLean JA 2nd, McAsey ME, et al. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Mol Cancer Res. 2012; 10:469–482. PMID: 22232518.

19. Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, et al. The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development. 2004; 131:2791–2801. PMID: 15142975.

20. Lucas FR, Salinas PC. WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev Biol. 1997; 192:31–44. PMID: 9405095.

21. Lyu J, Joo CK. Wnt-7a up-regulates matrix metalloproteinase-12 expression and promotes cell proliferation in corneal epithelial cells during wound healing. J Biol Chem. 2005; 280:21653–21660. PMID: 15802269.

22. Winn RA, Marek L, Han SY, Rodriguez K, Rodriguez N, Hammond M, et al. Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation. J Biol Chem. 2005; 280:19625–19634. PMID: 15705594.

23. Liu Z, Wang L, Yang J, Bandyopadhyay A, Kaklamani V, Wang S, et al. Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic Ras in human mammary epithelial cells. Oncotarget. 2016; 7:39097–39107. PMID: 27259243.

24. Choi M, Park YH, Ahn JS, Im YH, Nam SJ, Cho SY, et al. Evaluation of pathologic complete response in breast cancer patients treated with neoadjuvant chemotherapy: experience in a single institution over a 10-year period. J Pathol Transl Med. 2017; 51:69–78. PMID: 28013533.