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

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.

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

“…As reported earlier in other cell types, sorafenib downregulated phosphorylated levels of p38MAPK [25,34] and STAT5 [35,36] in MDA-MB-231 cells. Activation of p38MAPK has been found to transduce metastatic signaling and proliferation [11], whereas STAT5 signaling promotes tumor growth and metastasis in breast cancer cells [37,38].…”

“…Breast cancer stem cells contribute toward the development of metastasis because of their inherent resistance to chemotherapeutic drugs. Activation of intracellular signaling pathways such as ERK1/2 and p38 MAPK have been shown to advance tumor progression [10,11].…”

The p38 Pathway: From Biology to Cancer Therapy

“…Likewise, p38 modulates the expression of pro-angiogenic factors such as HBEGF, IL-8 and VEGFA in metastatic breast carcinoma cells. Inhibition of stress-activated p38 reduces primary tumor growth in orthotopic xenograft models and the number of lung metastatic colonies after tail-vein injection [111]. Although these findings support the prometastatic role of the p38 pathway, it has been reported that p38-knockdown human colorectal cancer cells show a greater capacity to colonize the lung in an orthotropic xenograft mouse model [112].…”

Molecular Genetics of Metastatic Breast Cancer

“…The inactivation of the p38/MAPK signaling pathway was provided by the expression of the kinase-inactive mutant (dn-p38) of p38/MAPK14 in metastatic breast cancer cells in the studies, and with the deterioration of the tumor p38/MAPK signal, the development of breast cancer and metastasis ability was shown to decrease in breast carcinoma xenografts [9]. The conducted kinase-inactive mutant significantly decreased the dn-p38, tumor blood vessel density, and lumen dimensions.…”

“…The deterioration of p38/MAPK signal causes no decrease in the expression of MMP9 and ICAM1 that are secreted by tumor cells. p38/MAPK signal contributes to fibronectin expression by responding to cytokines and tumor-fibroblast interactions [9].…”