TY - JOUR
T1 - Suppression of Integrin alpha 3 beta 1 in Breast Cancer Cells Reduces Cyclooxygenase-2 Gene Expression and Inhibits Tumorigenesis, Invasion, and Cross-Talk to Endothelial Cells
AU - Mitchell, K
AU - Svenson, KB
AU - Longmate, WM
AU - Gkirtzimanaki, K
AU - Sadej, Rafal
AU - Wang, X
AU - Zhao, J
AU - Eliopoulos, AG
AU - Berditchevski, Fedor
AU - DiPersio, CM
PY - 2010/8/1
Y1 - 2010/8/1
N2 - Integrin receptors for cell adhesion to extracellular matrix have important roles in promoting tumor growth and progression. Integrin alpha 3 beta 1 is highly expressed in breast cancer cells in which it is thought to promote invasion and metastasis; however, its roles in regulating malignant tumor cell behavior remain unclear. In the current study, we used short-hairpin RNA (shRNA) to show that suppression of alpha 3 beta 1 in a human breast cancer cell line, MDA-MB-231, leads to decreased tumorigenicity, reduced invasiveness, and decreased production of factors that stimulate endothelial cell migration. Real-time PCR revealed that suppression of alpha 3 beta 1 caused a dramatic reduction in expression of the cyclooxygenase-2 (COX-2) gene, which is frequently overexpressed in breast cancers and has been exploited as a therapeutic target. Decreased COX-2 was accompanied by reduced prostaglandin E2 (PGE(2)), a major prostanoid produced downstream of COX-2 and an important effector of COX-2 signaling. shRNA-mediated suppression of COX-2 showed that it has a role in tumor cell invasion and cross-talk to endothelial cells. Furthermore, treatment with PGE(2) restored these functions in alpha 3 beta 1-deficient MDA-MB-231 cells. These findings identify a role for alpha 3 beta 1 in regulating two properties of tumor cells that facilitate cancer progression: invasiveness and ability to stimulate endothelial cells. They also reveal a novel role for COX-2 as a downstream effector of alpha 3 beta 1 in tumor cells, thereby identifying alpha 3 beta 1 as a potential therapeutic target to inhibit breast cancer. Cancer Res; 70(15); 6359-67. (C) 2010 AACR.
AB - Integrin receptors for cell adhesion to extracellular matrix have important roles in promoting tumor growth and progression. Integrin alpha 3 beta 1 is highly expressed in breast cancer cells in which it is thought to promote invasion and metastasis; however, its roles in regulating malignant tumor cell behavior remain unclear. In the current study, we used short-hairpin RNA (shRNA) to show that suppression of alpha 3 beta 1 in a human breast cancer cell line, MDA-MB-231, leads to decreased tumorigenicity, reduced invasiveness, and decreased production of factors that stimulate endothelial cell migration. Real-time PCR revealed that suppression of alpha 3 beta 1 caused a dramatic reduction in expression of the cyclooxygenase-2 (COX-2) gene, which is frequently overexpressed in breast cancers and has been exploited as a therapeutic target. Decreased COX-2 was accompanied by reduced prostaglandin E2 (PGE(2)), a major prostanoid produced downstream of COX-2 and an important effector of COX-2 signaling. shRNA-mediated suppression of COX-2 showed that it has a role in tumor cell invasion and cross-talk to endothelial cells. Furthermore, treatment with PGE(2) restored these functions in alpha 3 beta 1-deficient MDA-MB-231 cells. These findings identify a role for alpha 3 beta 1 in regulating two properties of tumor cells that facilitate cancer progression: invasiveness and ability to stimulate endothelial cells. They also reveal a novel role for COX-2 as a downstream effector of alpha 3 beta 1 in tumor cells, thereby identifying alpha 3 beta 1 as a potential therapeutic target to inhibit breast cancer. Cancer Res; 70(15); 6359-67. (C) 2010 AACR.
U2 - 10.1158/0008-5472.CAN-09-4283
DO - 10.1158/0008-5472.CAN-09-4283
M3 - Article
C2 - 20631072
VL - 70
SP - 6359
EP - 6367
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -