Prognostic and predictive value of monocarboxylate transporter 4 in patients with breast cancer

Xiao,Sheng; Zhu,Hongjia; Shi,Yujun; Wu,Zhenru; Wu,Hegang; Xie,Mingjun

doi:10.3892/ol.2020.11776

Prognostic and predictive value of monocarboxylate transporter 4 in patients with breast cancer

Authors:
- Sheng Xiao
- Hongjia Zhu
- Yujun Shi
- Zhenru Wu
- Hegang Wu
- Mingjun Xie
View Affiliations

Affiliations: School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China, Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Chengdu, Sichuan 610000, P.R. China , Department of Pathology, The First People's Hospital of Yibin, Yibin, Sichuan 644000, P.R. China
Published online on: June 25, 2020 https://doi.org/10.3892/ol.2020.11776
Pages: 2143-2152
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The Warburg effect explains the large amount of lactic acid that tumour cells produce to establish and maintain the acidic characteristics of the tumour microenvironment, which contributes to the migration, invasion and angiogenesis of tumour cells. Monocarboxylate transporter 4 (MCT‑4) is a key marker of tumour glycolysis and lactic acid production; however, the role of MCT‑4 in breast cancer remains unclear. In the present study, immunohistochemistry (IHC) was used to detect the expression levels of MCT‑4 in tissue microarrays of 145 patients diagnosed with invasive ductal breast cancer. The IHC score was used to assess the intensity of staining and the proportion of positive cells. Western blotting and reverse transcription‑quantitative PCR were also performed to detect the expression levels of MCT‑4 in 30 pairs of breast cancer tissues and adjacent normal tissues. In vitro experiments (EdU incoporation and Cell Counting Kit‑8) were performed to examine the role of MCT‑4 in the breast cancer MCF‑7 cell line. The results of the present study indicated that high MCT‑4 expression was associated with pT status (P=0.018), oestrogen receptor (ER) status (P=0.001), progesterone receptor (PR) status (P=0.024), Ki67 index (P=0.043) and androgen receptor (AR) status (P=0.033). In addition, an association between MCT‑4 expression and pathological grade was observed (P=0.030). Furthermore, univariate (P=0.027) and multivariate (P=0.001) survival analysis revealed that MCT‑4 expression and lymph node involvement were significant independent predictors of breast cancer prognosis. In addition, silencing MCT‑4 expression attenuated breast cancer cell viability. Therefore, MCT‑4 may be used as a potential predictor of invasive breast cancer.

View Figures

View References

1	Xi J, Feng J, Li Q, Li X and Zeng S: The long non-coding RNA lncFOXO1 suppresses growth of human breast cancer cells through association with BAP1. Int J Oncol. 50:1663–1670. 2017. View Article : Google Scholar : PubMed/NCBI
2	Lu J, Tan M and Cai Q: The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 356:156–164. 2015. View Article : Google Scholar : PubMed/NCBI
3	Gatenby RA and Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 4:891–899. 2004. View Article : Google Scholar : PubMed/NCBI
4	Fang JS, Gillies RD and Gatenby RA: Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol. 18:330–337. 2008. View Article : Google Scholar : PubMed/NCBI
5	Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC and Baltazar F: Role of monocarboxylate transporters in human cancers: State of the art. J Bioenerg Biomembr. 44:127–139. 2012. View Article : Google Scholar : PubMed/NCBI
6	Halestrap AP: The monocarboxylate transporter family-Structure and functional characterization. IUBMB Life. 64:1–9. 2012. View Article : Google Scholar : PubMed/NCBI
7	Bonen A, Miskovic D, Tonouchi M, Lemieux K, Wilson MC, Marette A and Halestrap AP: Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. Am J Physiol Endocrinol Metab. 278:E1067–E1077. 2000. View Article : Google Scholar : PubMed/NCBI
8	Philp NJ, Yoon H and Lombardi L: Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol Cell Physiol. 280:C1319–C1326. 2001. View Article : Google Scholar : PubMed/NCBI
9	Doyen J, Trastour C, Ettore F, Peyrottes I, Toussant N, Gal J, Ilc K, Roux D, Parks SK, Ferrero JM and Pouysségur J: Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome. Biochem Biophys Res Commun. 451:54–61. 2014. View Article : Google Scholar : PubMed/NCBI
10	Fisel P, Kruck S, Winter S, Bedke J, Hennenlotter J, Nies AT, Scharpf M, Fend F, Stenzl A, Schwab M and Schaeffeler E: DNA methylation of the SLC16A3 promoter regulates expression of the human lactate transporter MCT4 in renal cancer with consequences for clinical outcome. Clin Cancer Res. 19:5170–5181. 2013. View Article : Google Scholar : PubMed/NCBI
11	Fisel P, Schaeffeler E and Schwab M: Clinical and functional relevance of the monocarboxylate transporter family in disease pathophysiology and drug therapy. Clin Transl Sci. 11:352–364. 2018. View Article : Google Scholar : PubMed/NCBI
12	Gotanda Y, Akagi Y, Kawahara A, Kinugasa T, Yoshida T, Ryu Y, Shiratsuchi I, Kage M and Shirouzu K: Expression of monocarboxylate transporter (MCT)-4 in colorectal cancer and its role: MCT4 contributes to the growth of colorectal cancer with vascular endothelial growth factor. Anticancer Res. 33:2941–2947. 2013.PubMed/NCBI
13	Hao J, Chen H, Madigan MC, Cozzi PJ, Beretov J, Xiao W, Delprado WJ, Russell PJ and Li Y: Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression. Br J Cancer. 103:1008–1018. 2010. View Article : Google Scholar : PubMed/NCBI
14	Hemdan T, Malmstrom PU, Jahnson S and Segersten U: Emmprin expression predicts response and survival following cisplatin containing chemotherapy for bladder cancer: A validation study. J Urol. 194:1575–1581. 2015. View Article : Google Scholar : PubMed/NCBI
15	Kim Y, Choi JW, Lee JH and Kim YS: Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: Immunohistochemical and The Cancer Genome Atlas data analyses. Hum Pathol. 46:104–112. 2015. View Article : Google Scholar : PubMed/NCBI
16	Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, Schmitt F and Baltazar F: GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol. 26:1279–1286. 2011.PubMed/NCBI
17	Szubert S, Szpurek D, Moszynski R, Nowicki M, Frankowski A, Sajdak S and Michalak S: Extracellular matrix metalloproteinase inducer (EMMPRIN) expression correlates positively with active angiogenesis and negatively with basic fibroblast growth factor expression in epithelial ovarian cancer. J Cancer Res Clin Oncol. 140:361–369. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zheng D, Zhu X, Ding X, Zhu X, Yin Y and Li G: Sensitive detection of CD147/EMMPRIN and its expression on cancer cells with electrochemical technique. Talanta. 105:187–191. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhu S, Chu D, Zhang Y, Wang X, Gong L, Han X, Yao L, Lan M, Li Y and Zhang W: EMMPRIN/CD147 expression is associated with disease-free survival of patients with colorectal cancer. Med Oncol. 30:3692013. View Article : Google Scholar : PubMed/NCBI
20	McClelland GB and Brooks GA: Changes in MCT 1, MCT 4, and LDH expression are tissue specific in rats after long-term hypobaric hypoxia. J Appl Physiol (1985). 92:1573–1584. 2002. View Article : Google Scholar : PubMed/NCBI
21	Lokuhetty D, White VA, Watanabe R, Cree IA, et al: WHO Classification of Tumours, 5th Edition, Volume 2: Breast Tumours. (Lyon, France). IARC Press. 2019.PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Maria RM, Altei WF, Selistre-de-Araujo HS and Colnago LA: Impact of chemotherapy on metabolic reprogramming: Characterization of the metabolic profile of breast cancer MDA-MB-231 cells using ¹H HR-MAS NMR spectroscopy. J Pharm Biomed Anal. 146:324–328. 2017. View Article : Google Scholar : PubMed/NCBI
24	Long Y, Gao Z, Hu X, Xiang F, Wu Z, Zhang J, Han X, Yin L, Qin J, Lan L, et al: Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer Med. 7:4690–4700. 2018. View Article : Google Scholar : PubMed/NCBI
25	Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al: Molecular portraits of human breast tumours. Nature. 406:747–752. 2000. View Article : Google Scholar : PubMed/NCBI
26	Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H and van de Vijver MJ: Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 9:R652007. View Article : Google Scholar : PubMed/NCBI
27	Bleach R and McIlroy M: The divergent function of androgen receptor in breast cancer; analysis of steroid mediators and tumor intracrinology. Front Endocrinol (Lausanne). 9:5942018. View Article : Google Scholar : PubMed/NCBI
28	Ruan Y, Zeng F, Cheng Z, Zhao X, Fu P and Chen H: High expression of monocarboxylate transporter 4 predicts poor prognosis in patients with lung adenocarcinoma. Oncol Lett. 14:5727–5734. 2017.PubMed/NCBI
29	Mathupala SP, Parajuli P and Sloan AE: Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: An in vitro study. Neurosurgery. 55:1410–1419. 2004. View Article : Google Scholar : PubMed/NCBI
30	Luo F, Zou Z, Liu X, Ling M, Wang Q, Wang Q, Lu L, Shi L, Liu Y, Liu Q and Zhang A: Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis. Carcinogenesis. 38:615–626. 2017. View Article : Google Scholar : PubMed/NCBI
31	Curry J, Tassone P, Gill K, Tuluc M, BarAd V, Mollaee M, Whitaker-Menezes D, Rodeck U, Luginbuhl A, Cognetti D, et al: Tumor metabolism in the microenvironment of nodal metastasis in oral squamous cell carcinoma. Otolaryngol Head Neck Surg. 157:798–807. 2017. View Article : Google Scholar : PubMed/NCBI
32	Yan P, Li YH, Tang ZJ, Shu X and Liu X: High monocarboxylate transporter 4 protein expression in stromal cells predicts adverse survival in gastric cancer. Asian Pac J Cancer Prev. 15:8923–8929. 2014. View Article : Google Scholar : PubMed/NCBI
33	Sanita P, Capulli M, Teti A, Galatioto GP, Vicentini C, Chiarugi P, Bologna M and Angelucci A: Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression. BMC cancer. 14:1542014. View Article : Google Scholar : PubMed/NCBI