TY - JOUR
T1 - Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors
AU - Limoge, Michelle
AU - Safina, Alfiya
AU - Truskinovsky, Alexander M.
AU - Aljahdali, Ieman
AU - Zonneville, Justin
AU - Gruevski, Aleksandar
AU - Arteaga, Carlos L.
AU - Bakin, Andrei V.
N1 - Funding Information:
PHS grant R01 CA95263 (to A.V.B.), Roswell Park Alliance Foundation (to A.V.B.) and in part by the
Funding Information:
We thank Mary M. Vaughan and Karoly Toth for assistance with the immunohistochemistry and histopathology. This work was supported by PHS grant R01 CA95263 (to A.V.B.), Roswell Park Alliance Foundation (to A.V.B.) and in part by the Roswell Park Cancer Institute Cancer Center Support Grant, CA16056.
Publisher Copyright:
© Limoge et al.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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 kinaseinactive 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 proangiogenic 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.
AB - 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 kinaseinactive 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 proangiogenic 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.
KW - Angiogenesis
KW - Breast cancer
KW - Fibronectin
KW - P38MAPK
KW - Tumor microenvironment
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U2 - 10.18632/oncotarget.18755
DO - 10.18632/oncotarget.18755
M3 - Article
C2 - 28977919
AN - SCOPUS:85028768531
SN - 1949-2553
VL - 8
SP - 61969
EP - 61981
JO - Oncotarget
JF - Oncotarget
IS - 37
ER -