Role of Integrin Related Tyrosine Kinases in Growth Control of Normal and Tumorigenic Human Mammary Epithelium.
Final rept. 1 Jul 94-30 Nov 97
SCRIPPS RESEARCH INST LA JOLLA CA
Pagination or Media Count:
We examined the role of the extracellular matrix protein laminin-5 Ln-5 in static adhesion and migration of normal HUMEC, immortalized MCF-10A and malignant breast epithelial cells that exhibit different degrees of metastatic potential MDA-MB-435MDA-MB-231MCF. HUMEC, MCF-10A, and MCF-7 cells adhered to purified Ln-5 through the integrin receptor in rapid adhesion assays. While HUMEC and MCF-10A cells remained statically adherent, MCF-7 cells migrated constitutively on Ln-5 in in-vitro assays. MDA-MB-231 and MDA-MB-435 cells bound and migrated on Ln-5 through a beta1 integrin receptor that is refractory to antibodies that block the function of alpha1, alpha2, alpha3, alpha4, alpha5, alpha6, and alphaV integrin subunits. Direct stimulation of the a3beta1 integrin receptor with the beta1 stimulating antibody TS216 is sufficient to induce migration of MCF-10A cells on Ln-5, and this migration is blocked by inhibitors of G proteins pertussis toxin, adenylate cyclase SQ22536, and protein kinase A H-89, suggesting that these signalling proteins may form an integrin-associated signalling pathway in MCF-10A cells. These inhibitors also block constitutive migration of the three malignant breast cell lines, suggesting that this pathway may play a role in the spread of malignant cells in breast cancer.
- Anatomy and Physiology