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Originally published online as doi:10.2353/ajpath.2007.060709 on April 19, 2007

Published online before print April 19, 2007
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(American Journal of Pathology. 2007;170:2135-2148.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060709

Evidence for a Role of Tumor-Derived Laminin-511 in the Metastatic Progression of Breast Cancer

Jenny Chia*, Nicole Kusuma*, Robin Anderson*{dagger}, Belinda Parker*{ddagger}, Bradley Bidwell*{ddagger}, Laura Zamurs§, Edouard Nice§ and Normand Pouliot*{dagger}

From the Peter MacCallum Cancer Centre,* Melbourne; the Departments of Pathology{dagger} and Biochemistry,{ddagger} University of Melbourne, Victoria; and the Ludwig Institute for Cancer Research,§ Royal Melbourne Hospital, Parkville, Australia

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 {alpha}5 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 {alpha}3 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 {alpha}3ß1 integrin, results from antibody perturbation experiments and flow cytometry analysis suggest that this response is mediated by an as yet unidentified {alpha}3ß integrin heterodimer (other than {alpha}3ß1) in MDA-MB-231 cells. These results are consistent with earlier reports implicating {alpha}3 integrins in breast cancer progression and support the role of LM-511 as a functional substrate regulating breast cancer metastasis.






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Copyright © 2007 by the American Society for Investigative Pathology.