Abstract

The breast carcinoma microenvironment strikingly influences cancer progression and response to therapy. Various cell types in the carcinoma microenvironment show significant activity of p38 mitogen-activated protein kinase (MAPK), although the role of p38MAPK in breast cancer progression is still poorly understood. The present study examined the contribution of tumor p38MAPK to breast carcinoma microenvironment and metastatic capacity. Inactivation of p38MAPK signaling in metastatic breast carcinoma cells was achieved by forced expression of the kinase-inactive mutant of p38/MAPK14 (a dominant-negative p38, dn-p38). Disruption of tumor p38MAPK signaling reduced growth and metastases of breast carcinoma xenografts. Importantly, dn-p38 markedly decreased tumor blood-vessel density and lumen sizes. Mechanistic studies revealed that p38 controls expression of pro-angiogenic extracellular factors such as matrix protein Fibronectin and cytokines VEGFA, IL8, and HBEGF. Tumor-associated fibroblasts enhanced tumor growth and vasculature as well as increased expression of the pro-angiogenic factors. These effects were blunted by dn-p38. Metadata analysis showed elevated expression of p38 target genes in breast cancers and this was an unfavorable marker of disease recurrence and poor-outcome. Thus, our study demonstrates that tumor p38MAPK signaling promotes breast carcinoma growth, invasive and metastatic capacities. Importantly, p38 enhances carcinoma vascularization by facilitating expression and deposition of pro-angiogenic factors. These results argue that p38MAPK is a valuable target for anticancer therapy affecting tumor vasculature. Anti-p38 drugs may provide new therapeutic strategies against breast cancer, including metastatic disease.

Highlights

  • Breast cancer is the second leading cause of cancerrelated death among women in North America [1]

  • These results indicate that tumor p38MAPK is critical for tumor vascularization

  • The current study found that p38MAPK signaling in tumor cells promotes breast carcinoma growth and metastasis by altering the tumor microenvironment (TME)

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Summary

Introduction

Breast cancer is the second leading cause of cancerrelated death among women in North America [1]. Experimental evidence indicates that TAFs are the predominant cell type in the TME, which promote tumor infiltration by pro-tumorigenic myeloid immune cells such as macrophages, neutrophils and myeloid-derived suppressor cells (MDSCs) [6, 7]. These myeloid cells stimulate tumor vascularization and metastasis by secreting metalloproteinase MMP9/gelatinase-B [7,8,9], which increases recruitment of endothelial cells and pericytes [8, 10, 11]. All three cellular components of the breast TME can contribute to MMP9driven tumor vascularization

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