Suppression of integrin alpha3beta1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells.
Integrin receptors for cell adhesion to extracellular matrix have important roles in promoting tumor growth and progression. Integrin alpha3beta1 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 alpha3beta1 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 alpha3beta1 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 alpha3beta1-deficient MDA-MB-231 cells. These findings identify a role for alpha3beta1 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 alpha3beta1 in tumor cells, thereby identifying alpha3beta1 as a potential therapeutic target to inhibit breast cancer.
Mitchell
Kara
K
Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208-3479, USA.
Svenson
Kimberly B
KB
Longmate
Whitney M
WM
Gkirtzimanaki
Katerina
K
Sadej
Rafal
R
Wang
Xianhui
X
Zhao
Jihe
J
Eliopoulos
Aristides G
AG
Berditchevski
Fedor
F
Dipersio
C Michael
CM
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039201:Integrin alpha3beta1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D039201:Integrin alpha3beta1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2