Expression of MTDH and IL-10 Is an Independent Predictor of Worse Prognosis in ER-Negative or PR-Negative Breast Cancer Patients.

Pei-Yi Chu,Po-Ming Chen,Feng-Yao Tang,Shin-Mae Wang,En-Pei Isabel Chiang

doi:10.3390/jcm9103153

Abstract

(1) Background: Tumor hypoxia leads to metastasis and certain immune responses, and interferes with normal biological functions. It also affects glucose intake, down-regulates oxidative phosphorylation, and inhibits fatty-acid desaturation regulated by hypoxia-inducible factor 1α (HIF-1α). Although tumor hypoxia has been found to promote tumor metastasis, the roles of HIF-1α-regulated genes and their application are not completely integrated in clinical practice. (2) Methods: We examined the correlation between HIF-1α, metadherin (MTDH), and interleukin (IL)-10 mRNA expression, as well as their expression patterns in the prognosis of breast cancer using the Gene Expression Profiling Interactive Analysis (GEPIA) databases via a web interface; tissue microarrays (TMAs) were stained for MTDH and IL-10 protein expression using immunohistochemistry. (3) Results: HIF-1α, MTDH, and IL-10 mRNA expression are highly correlated and strongly associated with poor prognosis. MTDH and IL-10 protein expression of breast cancer patients usually harbored negative estrogen receptor (ER) or progesterone receptor (PR) status, and late-stage tumors have higher IL-10 expression. With regard to MTDH and IL-10 protein expression status for using univariate and multivariate analysis, the results showed that the protein expression of MTDH and IL-10 in ER-negative or PR-negative breast cancer patients have the worse prognosis. (4) Conclusions: we propose a new insight into hypoxia tumors in the metabolism and immune evidence for breast cancer therapy.

Highlights

Breast cancer is one of the most commonly diagnosed cancers
We identified that MTDH and interleukin 10 (IL-10) protein expression is an independent predictor of worse prognosis in estrogen receptor (ER)-negative and progesterone receptor (PR)-negative breast cancer patients, which could predict overall survival
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Summary

Introduction

Breast cancer is one of the most commonly diagnosed cancers. From 2006 to 2015, breast cancer incidence increased by approximately 1.8% per year among Asian women [1]. Malignant cancer cells cause an increase of anaerobic adenosine triphosphate (ATP) generation in response to a declined oxygen, rendering the aberrant vasculature development that leads to metastasis by increasing the transcription of hypoxia-inducible factor (HIF)-regulated genes [6,7]. IL-10 stimulates the expression of carboxypeptidase B2 and promotes lymphovascular invasion in inflammatory breast cancer cell-line SUM-149, but not in non-inflammatory breast cancer cell MDA-MB-231 [19] These studies suggested potential roles of HIF-1α target genes in breast cancer and tumor hypoxia, and that HIF-1α-induced genes could be potential therapeutic targets for breast cancer. We explored the clinical significance of HIF-1α target gene MTDH, IL-10, CXCL12, CCL2, VEGF, MMP2, LOX, and C-X-C chemokine receptor type 4 (CXCR4) in breast cancer, using RNA-seq datasets from open sources, and further validated these findings in our own breast cancer cohort by immunohistochemistry. We identified that MTDH and IL-10 protein expression is an independent predictor of worse prognosis in ER-negative and PR-negative breast cancer patients, which could predict overall survival

Patients

Immunohistochemistry and Scoring

Statistical Analysis

Findings

Discussion