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An Inherent Role of Integrin-Linked Kinase-Estrogen Receptor Interaction in Cell Migration

Departments of ¹ Molecular and Cellular Oncology and ² Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center; and ³ Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Rakesh Kumar, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: rkumar{at}mdanderson.org.

Integrin-linked kinase (ILK) and estrogen receptor (ER)- modulate cell migration. However, the crosstalk between ER and ILK and the role of ILK in ER-mediated cell migration remain unexplored. Here, we report that ILK participates in ER signaling in breast cancer cells. We found that ILK binds ER in vitro and in vivo through a LXXLL motif in ILK. Estrogen prevented ER-ILK binding, resulting in phosphatidylinositol 3-kinase (PI3K)–dependent increase in ILK kinase activity. Furthermore, the regulation of ER-ILK interaction was dependent on the PI3K pathway. Unexpectedly, transient knockdown or inhibition of ILK caused hyperphosphorylation of ER Ser¹¹⁸ in an extracellular signal–regulated kinase/mitogen-activated protein kinase pathway–dependent manner and an enhanced ER recruitment to the target chromatin and gene expression, a process reversed by overexpression of ILK. Compatible with these interactions, estrogen regulated cell migration via the PI3K/ILK/AKT pathway with stable ILK overexpression hyperactivating cell migration. Thus, status of ILK signaling may be an important modifier of ER signaling in breast cancer cells and this pathway could be exploited for therapeutic intervention in breast cancer cells. (Cancer Res 2006; 66(22): 11030-8)

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