'lizbeth
11-09-2013, 09:02 PM
Cancer Res. (http://www.ncbi.nlm.nih.gov/pubmed/24177178#) 2013 Oct 31. [Epub ahead of print]
Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation.
Lee CY (http://www.ncbi.nlm.nih.gov/pubmed?term=Lee%20CY%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Lin Y (http://www.ncbi.nlm.nih.gov/pubmed?term=Lin%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Bratman S (http://www.ncbi.nlm.nih.gov/pubmed?term=Bratman%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Feng W (http://www.ncbi.nlm.nih.gov/pubmed?term=Feng%20W%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Kuo A (http://www.ncbi.nlm.nih.gov/pubmed?term=Kuo%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Scheeren F (http://www.ncbi.nlm.nih.gov/pubmed?term=Scheeren%20F%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Engreitz JM (http://www.ncbi.nlm.nih.gov/pubmed?term=Engreitz%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Varma S (http://www.ncbi.nlm.nih.gov/pubmed?term=Varma%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), West R (http://www.ncbi.nlm.nih.gov/pubmed?term=West%20R%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Diehn M (http://www.ncbi.nlm.nih.gov/pubmed?term=Diehn%20M%5BAuthor%5D&cauthor=true&cauthor_uid=24177178).
Source
Stanford Cancer Institute/Stem Cell Institute, Stanford University.
Abstract
Currently only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TICs) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2 or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2 targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of breast cancer patients than they currently reach.
Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation.
Lee CY (http://www.ncbi.nlm.nih.gov/pubmed?term=Lee%20CY%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Lin Y (http://www.ncbi.nlm.nih.gov/pubmed?term=Lin%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Bratman S (http://www.ncbi.nlm.nih.gov/pubmed?term=Bratman%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Feng W (http://www.ncbi.nlm.nih.gov/pubmed?term=Feng%20W%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Kuo A (http://www.ncbi.nlm.nih.gov/pubmed?term=Kuo%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Scheeren F (http://www.ncbi.nlm.nih.gov/pubmed?term=Scheeren%20F%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Engreitz JM (http://www.ncbi.nlm.nih.gov/pubmed?term=Engreitz%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Varma S (http://www.ncbi.nlm.nih.gov/pubmed?term=Varma%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), West R (http://www.ncbi.nlm.nih.gov/pubmed?term=West%20R%5BAuthor%5D&cauthor=true&cauthor_uid=24177178), Diehn M (http://www.ncbi.nlm.nih.gov/pubmed?term=Diehn%20M%5BAuthor%5D&cauthor=true&cauthor_uid=24177178).
Source
Stanford Cancer Institute/Stem Cell Institute, Stanford University.
Abstract
Currently only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TICs) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2 or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2 targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of breast cancer patients than they currently reach.