This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miller, J. K. Articles by Sweeney, C. Search for Related Content PubMed PubMed Citation Articles by Miller, J. K. Articles by Sweeney, C.

Suppression of the Negative Regulator LRIG1 Contributes to ErbB2 Overexpression in Breast Cancer

¹ University of California Davis Cancer Center and ² Department of Medical Pathology and Laboratory Medicine, School of Medicine, University of California at Davis, Sacramento, California

Requests for reprints: Colleen Sweeney, University of California Davis Cancer Center, University of California at Davis, Research Building III, Room 1100A, 4645 2nd Avenue, Sacramento, CA 95817. Phone: 916-734-0726; Fax: 916-734-0190; E-mail: casweeney{at}ucdavis.edu.

Key Words: ErbB2 • LRIG1 • negative regulator • breast cancer

The ErbB2 receptor tyrosine kinase is overexpressed in 25% of breast tumors and contributes to poor patient prognosis and therapeutic resistance. Here, we examine the role of the recently discovered ErbB negative regulator LRIG1 in ErbB2⁺ breast cancer. We observe that LRIG1 protein levels are significantly suppressed in ErbB2-induced mammary tumors in transgenic mice as well as in the majority of ErbB2⁺ human breast tumors. These observations raise the possibility that LRIG1 loss could contribute to the initiation or growth of ErbB2⁺ breast tumors. RNA interference–mediated knockdown of endogenous LRIG1 in the ErbB2-overexpressing breast tumor cell lines MDA-MB-453 and BT474 further elevates ErbB2 in these cells and augments cellular proliferation. In contrast, ectopic expression of LRIG1 reverses these trends. Interestingly, we observe that LRIG1 protein levels are suppressed in response to ErbB receptor activation in breast tumor cells but are unaffected by ErbB activation in immortalized nontransformed breast epithelial cells. Our observations indicate that the suppression of LRIG1 protein levels is a common feature of breast tumors. Moreover, our observations point to the existence of a feed-forward regulatory loop in breast tumor cells where aberrant ErbB2 signaling suppresses LRIG1 protein levels, which in turn contributes to ErbB2 overexpression. [Cancer Res 2008;68(20):8286–94]