Oncotarget

Research Papers:

Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors

Michelle Limoge, Alfiya Safina, Alexander M. Truskinovsky, Ieman Aljahdali, Justin Zonneville, Aleksandar Gruevski, Carlos L. Arteaga and Andrei V. Bakin _

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Oncotarget. 2017; 8:61969-61981. https://doi.org/10.18632/oncotarget.18755

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Abstract

Michelle Limoge1, Alfiya Safina3, Alexander M. Truskinovsky2, Ieman Aljahdali1, Justin Zonneville1, Aleksandar Gruevski5, Carlos L. Arteaga4 and Andrei V. Bakin1

1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA

2Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York, USA

3Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA

4Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

5State University of New York at Buffalo, Department of Biological Sciences, Buffalo, New York, USA

Correspondence to:

Andrei V. Bakin, email: andrei.bakin@roswellpark.org

Keywords: tumor microenvironment, breast cancer, p38MAPK, angiogenesis, fibronectin

Received: April 26, 2017    Accepted: May 19, 2017    Published: June 28, 2017

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.


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