Document Detail

Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer.
MedLine Citation:
PMID:  18922900     Owner:  NLM     Status:  MEDLINE    
The ErbB2 receptor tyrosine kinase is overexpressed in approximately 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.
Jamie K Miller; David L Shattuck; Ellen Q Ingalla; Lily Yen; Alexander D Borowsky; Lawrence J T Young; Robert D Cardiff; Kermit L Carraway; Colleen Sweeney
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-16     Completed Date:  2008-11-07     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8286-94     Citation Subset:  IM    
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MeSH Terms
Breast Neoplasms / chemistry,  etiology*,  pathology
Cell Line, Tumor
Genes, erbB-2
Membrane Glycoproteins / analysis,  antagonists & inhibitors,  physiology*
Mice, Transgenic
Nerve Tissue Proteins / analysis,  physiology*
Receptor, erbB-2 / analysis,  physiology*
Signal Transduction
Grant Support
CA118384/CA/NCI NIH HHS; GM068994/GM/NIGMS NIH HHS; R01 CA118384/CA/NCI NIH HHS; R01 CA118384-01A1/CA/NCI NIH HHS; R01 CA118384-02/CA/NCI NIH HHS; R01 CA118384-03/CA/NCI NIH HHS
Reg. No./Substance:
0/LRIG1 protein, human; 0/Lrig1 protein, mouse; 0/Membrane Glycoproteins; 0/Nerve Tissue Proteins; EC protein, human; EC protein, mouse; EC, erbB-2

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