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β-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer

Oncogene volume 23, pages 8959–8970 (2004)Cite this article

Abstract

We analysed breast tumors and breast cancer cell lines for the expression of β-parvin (ParvB), an adaptor protein that binds to the integrin-linked kinase (ILK). Quantitative RT–PCR indicated that ParvB mRNA was downregulated, by at least 60%, in four of nine breast tumors, relative to patient-matched normal mammary gland tissue. We also found that ParvB protein levels were reduced by ⩾90% in five of seven advanced tumors, relative to matched normal breast tissue. Conversely, ILK protein and kinase activity levels were elevated in these tumors, suggesting that downregulation of ParvB stimulates ILK signaling. Western blot analyses indicated very low levels of ParvB protein in MDA-MB-231 and MCF7 breast cancer cells, facilitating functional studies of the effects of ParvB on ILK signaling. Expression of ParvB in MDA-MB-231 and MCF7 cells increased cell adhesion to collagen. ParvB inhibited ILK kinase activity, anchorage-independent cell growth and in vitro matrigel invasion by MDA-MB-231 cells. EGF-induced phosphorylation of two ILK targets, PKB (Ser473) and glycogen synthase kinase 3β (Ser9), was also inhibited by ParvB. These results indicated that ParvB inhibits ILK signaling downstream of receptor tyrosine kinases. Our results suggest that loss of ParvB expression is a novel mechanism for upregulating ILK activity in tumors.

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Acknowledgements

We thank HSC colleagues, Dr S Egan for critical reading of the manuscript, Dr C Pace-Asciak for the gift of MDA-MB-231 and MCF7 cells, Drs Rae Yeung and Trang Duong for providing β-actin primers and Sherry Zhao (HSC FACS facility) for her expert cell cycle analyses. CNJ was supported by grants from the American Association for Cancer Research and US Department of Defense. AKR received an R01 grant from the National Institutes of Health and grants from the Hansen Foundation and NCCRA/EIF. GH was supported by grants from the National Cancer Institute of Canada (with funds from the Terry Fox Run) and the Canadian Institutes of Health Research. GH was a CIHR scholar.

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Authors and Affiliations

  1. Cancer Research Program, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Perry S Mongroo, Izabela Naruszewicz, Chungyee Leung-Hagesteijn, Leanne Carnio & Gregory E Hannigan

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto,

    Perry S Mongroo, Izabela Naruszewicz, Chungyee Leung-Hagesteijn, Leanne Carnio & Gregory E Hannigan

  3. Departments of Medicine and Genetics, Gastroenterology Division, Abramson Cancer Center, University of Pennsylvania, 600 CRB, 415 Curie Blvd., Philadelphia, 19104, PA, USA

    Cameron N Johnstone, Raphael K Sung & Anil K Rustgi

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  1. Perry S Mongroo
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Correspondence to Gregory E Hannigan.

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Mongroo, P., Johnstone, C., Naruszewicz, I. et al. β-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer. Oncogene 23, 8959–8970 (2004). https://doi.org/10.1038/sj.onc.1208112

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