J Breast Cancer.  2013 Jun;16(2):146-151. 10.4048/jbc.2013.16.2.146.

The Expression of Glut-1, CAIX, and MCT4 in Mucinous Carcinoma

• Kim S
• Jung WH
• Koo JS

• KMID: 2286393
• DOI: http://doi.org/10.4048/jbc.2013.16.2.146

Abstract

PURPOSE
The aim of this study was to assess the expression of metabolism-related proteins including glucose transporter 1 (Glut-1), carbonic anhydrase IX (CAIX) and monocarboxylate transporter 4 (MCT4) in breast mucinous carcinoma and to evaluate the implications of the results.
METHODS
Immunohistochemical staining for Glut-1, CAIX, and MCT4 was performed on tissue sections from 59 cases of mucinous carcinoma to evaluate the association between the expression of metabolism-related proteins and clinicopathologic factors. Mucinous carcinoma was subclassified into type A and type B according to histopathological characteristics.
RESULTS
Of the 59 patients, 35 patients (59.3%) were type A mucinous carcinoma and 24 patients (40.7%) were type B mucinous carcinoma. Stromal expression of MCT4 was significantly associated with a high histologic grade (p=0.022) and type B mucinous carcinoma (p=0.016). There were significant positive correlations between the expression of Glut-1, CAIX and tumoral expression of MCT4 (p<0.05).
CONCLUSION
We assessed the expression of metabolism-related proteins including Glut-1, CAIX, and MCT4 in breast mucinous carcinoma and found that the stromal expression of MCT4 was higher in type B mucinous carcinoma than in type A, which reflected a difference in the tumor microenvironment.

Keyword

Breast; Monocarboxylate transporter 4 protein; Mucinous adenocarcinoma

MeSH Terms

Adenocarcinoma, Mucinous
Breast
Carbonic Anhydrases
Glucose Transport Proteins, Facilitative
Humans
Mucins
Proteins
Tumor Microenvironment
Carbonic Anhydrases
Glucose Transport Proteins, Facilitative
Mucins
Proteins

Figure

• 

  Figure 1 Immunohistochemical staining of monocarboxylate transporter 4 (MCT4), glucose transporter 1 (Glut-1), and carbonic anhydrase IX (CAIX) according to the subtype of mucinous carcinoma. Type B mucinous carcinoma shows high expression of MCT4 in the tumor stroma, but type A mucinous carcinoma demonstrates no expression of MCT4 in the tumor stroma. MCT4=monocarboxylate transporter 4; Glut-1=glucose transporter 1; CAIX=carbonic anhydrase IX.

Reference

1. Warburg O. On the origin of cancer cells. Science. 1956; 123:309–314.

2. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004; 4:891–899.

3. Robertson N, Potter C, Harris AL. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res. 2004; 64:6160–6165.

4. Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275:21797–21800.

5. Brown RS, Wahl RL. Overexpression of Glut-1 glucose transporter in human breast cancer. An immunohistochemical study. Cancer. 1993; 72:2979–2985.

6. Grover-McKay M, Walsh SA, Seftor EA, Thomas PA, Hendrix MJ. Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res. 1998; 4:115–120.

7. Stackhouse BL, Williams H, Berry P, Russell G, Thompson P, Winter JL, et al. Measurement of glut-1 expression using tissue microarrays to determine a race specific prognostic marker for breast cancer. Breast Cancer Res Treat. 2005; 93:247–253.

8. Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 2001; 19:3660–3668.

9. Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, et al. GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol. 2011; 26:1279–1286.

10. Tan PH, Tse GM, Bay BH. Mucinous breast lesions: diagnostic challenges. J Clin Pathol. 2008; 61:11–19.

11. Norris HJ, Taylor HB. Prognosis of mucinous (gelatinous) carcinoma of the breast. Cancer. 1965; 18:879–885.

12. Rasmussen BB, Rose C, Christensen IB. Prognostic factors in primary mucinous breast carcinoma. Am J Clin Pathol. 1987; 87:155–160.

13. Capella C, Eusebi V, Mann B, Azzopardi JG. Endocrine differentiation in mucoid carcinoma of the breast. Histopathology. 1980; 4:613–630.

14. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991; 19:403–410.

15. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010; 28:2784–2795.

16. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25:118–145.

17. Ravazoula P, Batistatou A, Aletra C, Ladopoulos J, Kourounis G, Tzigounis B. Immunohistochemical expression of glucose transporter Glut1 and cyclin D1 in breast carcinomas with negative lymph nodes. Eur J Gynaecol Oncol. 2003; 24:544–546.

18. Chen CL, Chu JS, Su WC, Huang SC, Lee WY. Hypoxia and metabolic phenotypes during breast carcinogenesis: expression of HIF-1alpha, GLUT1, and CAIX. Virchows Arch. 2010; 457:53–61.

19. Kang SS, Chun YK, Hur MH, Lee HK, Kim YJ, Hong SR, et al. Clinical significance of glucose transporter 1 (GLUT1) expression in human breast carcinoma. Jpn J Cancer Res. 2002; 93:1123–1128.

20. Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, et al. The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer. 2009; 100:405–411.

21. Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouysségur J, et al. HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer. 2007; 120:1451–1458.

22. Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 2001; 61:6394–6399.

23. Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell. 1994; 76:865–873.

24. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011; 10:1772–1783.

25. Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, et al. Using the "reverse Warburg effect" to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 2012; 11:1108–1117.

26. Kim D, Jung WH, Koo JS. Expression of MUC1, MUC2, MUC5AC and MUC5B in mucinous lesions of the breast. Pathobiology. 2012; 79:144–153.