PTH-related protein enhances MCF-7 breast cancer cell adhesion, migration, and invasion via an intracrine pathway.
Breast cancer is the most common carcinoma that metastasizes to the bone. Parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process in breast cancer. PTHrP overexpression increases mitogenesis and decreases apoptosis in the human breast cancer cell line MCF-7. In this study, MCF-7 cells were used as a model system to study the effects of PTHrP on breast cancer cell adhesion, migration, and invasion. Clones of MCF-7 cells were established that overexpress wild-type PTHrP or PTHrP mutated in the nuclear localization sequence (NLS). Wild-type PTHrP-overexpressing cells showed significantly higher laminin adhesion and migration, and Matrigel invasion than empty vector-transfectants or cells overexpressing NLS-mutated PTHrP. Wild-type PTHrP also increased the cell surface expression of the pro-invasive integrins alpha6 and beta4; deletion of the NLS negated these effects. Exogenous PTHrP (1-34), (67-86), (107-139), and (140-173) had no effect on integrin expression, or on cell adhesion, migration, and invasion. These results indicate that PTHrP exerts its effects on cell adhesion, migration, invasion, and integrin expression via an intracrine pathway. PTHrP may play a role in breast cancer metastasis by upregulating proinvasive integrin expression, and controlling PTHrP production in breast cancer may provide therapeutic benefit.
Shen
Xiaoli
X
Department of Pharmacology and Toxicology, and Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, TX 77555, USA.
Qian
Lihui
L
Falzon
Miriam
M
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D009362:Neoplasm Metastasis; D019913:Nuclear Localization Signals / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D016023:Integrins; D007797:Laminin; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D012333:RNA, Messenger