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      Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer

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          Abstract

          Using fluorescence in situ hybridization (FISH), we previously showed that the LRIG1 gene had an increased copy number in 11 of 28 (39%) breast cancer tumours [1]. The LRIG1 gene (leucine-rich repeats and immunoglobulin-like domains 1) at chromosome 3p14 is a proposed tumour suppressor gene that negatively regulates various receptor tyrosine kinases, including the breast cancer proto-oncogene product ERBB2 [2,3]. Recently, however, Miller and colleagues [4] showed that 10 of 13 (76%) ERBB2+ tumours had decreased LRIG1 protein levels compared to normal breast tissue. As their data showed down-regulation at the protein level whereas our data showed an increased copy number at the genomic level, we analysed 45 additional breast tumours by FISH as previously described [1]. Thus, out of 73 tumours analysed to date, 25 (34%) did indeed have increased LRIG1 copy number. To further analyse the relationship between LRIG1 and ERBB2 at the genomic level, we evaluated the ERBB2 gene copy numbers in 18 tumours with increased LRIG1 copy number using FISH analysis according to standard procedures. Interestingly, 16 (89%) out of the 18 tumours displayed increased copy number of ERBB2 (Figure 1). This suggests that the majority of breast cancer tumours with increased copy number of ERBB2 simultaneously had increased LRIG1 copy number (our data) and decreased LRIG1 protein levels [4]. Figure 1 Increased copy number of LRIG1 and ERBB2 in human breast cancer in the same patient. Interphase nuclei from a breast cancer tumour were analysed by FISH. (a) A specific LRIG1 probe (red) showed increased LRIG1 copy number (five copies) whereas a specific centromere probe (CEP3) (green) showed normal chromosome 3 copy number (two copies). (b) A specific ERBB2 probe (red) showed amplification of the ERBB2 gene whereas a specific centromere probe (CEP17; green) showed three copies of chromosomes 17. We draw the following major conclusions from these results. First, as previously shown, a significant proportion of breast tumours have an increased LRIG1 gene dosage. Second, there is a correlation between increased gene copy numbers of ERBB2 and LRIG1. Third, based on the Miller protein data, most of the tumours with increased LRIG1 gene dosage express reduced levels of the LRIG1 protein. This indicates a negative selection against LRIG1 protein expression, supporting the notion that LRIG1 is a tumour suppressor in breast cancer. Although the mechanism behind the down-regulation of LRIG1 protein in breast cancer is not known, it has been reported that increased gene copy numbers in some cases are associated with decreased mRNA expression [5]. In any case, the high frequency (34%) of tumours with increased LRIG1 gene copy number implies a positive selection for tumour cells with this genomic alteration. It remains, however, to be elucidated whether the molecular driver behind the selective advantage associated with this alteration is LRIG1 down-regulation per se. Other possibilities include activation of nearby proto-oncogenes or the generation of novel oncogenic fusion genes. In summary, the co-incidental increase in copy number of ERBB2 and LRIG1 in breast cancer is a novel finding, pointing at a functional co-operation between these genetic events, where the biological and clinical importance need to be clarified further. Abbreviations FISH: fluorescence in situ hybridization. Competing interests The authors declare that they have no competing interests.

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          Most cited references 4

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          LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation.

          Kekkon proteins negatively regulate the epidermal growth factor receptor (EGFR) during oogenesis in Drosophila. Their structural relative in mammals, LRIG1, is a transmembrane protein whose inactivation in rodents promotes skin hyperplasia, suggesting involvement in EGFR regulation. We report upregulation of LRIG1 transcript and protein upon EGF stimulation, and physical association of the encoded protein with the four EGFR orthologs of mammals. Upregulation of LRIG1 is followed by enhanced ubiquitylation and degradation of EGFR. The underlying mechanism involves recruitment of c-Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation. We conclude that LRIG1 evolved in mammals as a feedback negative attenuator of signaling by receptor tyrosine kinases.
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            The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases.

            The molecular mechanisms by which mammalian receptor tyrosine kinases are negatively regulated remain largely unexplored. Previous genetic and biochemical studies indicate that Kekkon-1, a transmembrane protein containing leucine-rich repeats and an immunoglobulin-like domain in its extracellular region, acts as a feedback negative regulator of epidermal growth factor (EGF) receptor signaling in Drosophila melanogaster development. Here we tested whether the related human LRIG1 (also called Lig-1) protein can act as a negative regulator of EGF receptor and its relatives, ErbB2, ErbB3, and ErbB4. We observed that in co-transfected 293T cells, LRIG1 forms a complex with each of the ErbB receptors independent of growth factor binding. We further observed that co-expression of LRIG1 with EGF receptor suppresses cellular receptor levels, shortens receptor half-life, and enhances ligand-stimulated receptor ubiquitination. Finally, we observed that co-expression of LRIG1 suppresses EGF-stimulated transformation of NIH3T3 fibroblasts and that the inducible expression of LRIG1 in PC3 prostate tumor cells suppresses EGF- and neuregulin-1-stimulated cell cycle progression. Our observations indicate that LRIG1 is a negative regulator of the ErbB family of receptor tyrosine kinases and suggest that LRIG1-mediated receptor ubiquitination and degradation may contribute to the suppression of ErbB receptor function.
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              Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer.

              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.
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                Author and article information

                Journal
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central
                1465-5411
                1465-542X
                2009
                12 May 2009
                : 11
                : 3
                : 403
                Affiliations
                [1 ]Department of Radiation Sciences, Oncology, Umeå University Hospital, SE-90187, Umeå, Sweden
                [2 ]Department of Medical Biosciences, Medical and Clinical Genetics, SE-90187, Umeå, Sweden
                [3 ]Department of Medical Biosciences, Clinical Chemistry, Umeå University, SE-90187, Umeå, Sweden
                [4 ]Department of Pathology, Umeå University, SE-90187, Umeå, Sweden
                Article
                bcr2248
                10.1186/bcr2248
                2716489
                19490591
                Copyright © 2009 BioMed Central Ltd
                Categories
                Letter

                Oncology & Radiotherapy

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