Evidence for a role of tumor-derived laminin-511 in the metastatic progression of breast cancer.

ABSTRACT

Most studies investigating laminins (LMs) in breast cancer have focused on LM-111 or LM-332. Little is known, however, about the expression and function of alpha5 chain-containing LM-511/521 during metastatic progression. Expression of LM-511/521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model using real-time quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The results from our investigation indicate that LM-511 rather than LM-111, -332, or -521 correlates with metastatic potential in mouse mammary tumors. LM-511 was a potent adhesive substrate for both murine and human breast carcinoma cells and promoted strong haptotactic responses in metastatic lines. Haptotaxis was mediated by alpha3 integrin in both MCF-7 and MDA-MB-231 cells and was strongly inhibited by blocking antibodies against this integrin subunit. However, whereas nonmetastatic MCF-7 cells migrated toward LM-511 primarily via alpha3beta1 integrin, results from antibody perturbation experiments and flow cytometry analysis suggest that this response is mediated by an as yet unidentified alpha3beta integrin heterodimer (other than alpha3beta1) in MDA-MB-231 cells. These results are consistent with earlier reports implicating alpha3 integrins in breast cancer progression and support the role of LM-511 as a functional substrate regulating breast cancer metastasis.