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Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy
Understanding the signaling differences that distinguish human HER2-amplified (HER2-positive (HER2+)) breast cancers from other breast cancer subtypes may help to identify protein drug targets for the specific treatment of HER2+ breast cancers. We performed two kinome-wide small interfering RNA (siR...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275559/ https://www.ncbi.nlm.nih.gov/pubmed/25500906 http://dx.doi.org/10.1038/oncsis.2014.45 |
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author | Lapin, V Shirdel, E A Wei, X Mason, J M Jurisica, I Mak, T W |
author_facet | Lapin, V Shirdel, E A Wei, X Mason, J M Jurisica, I Mak, T W |
author_sort | Lapin, V |
collection | PubMed |
description | Understanding the signaling differences that distinguish human HER2-amplified (HER2-positive (HER2+)) breast cancers from other breast cancer subtypes may help to identify protein drug targets for the specific treatment of HER2+ breast cancers. We performed two kinome-wide small interfering RNA (siRNA) screens on five HER2+ breast cancer cell lines, seven breast cancer cell lines in which HER2 was not amplified and two normal breast cell lines. To pinpoint the main kinases driving HER2 signaling, we performed a comprehensive siRNA screen that identified loss of the HER2/HER3 heterodimer as having the most prominent inhibitory effect on the growth of HER2+ breast cancer cells. In a second siRNA screen focused on identifying genes that could sensitize HER2+ cells to trastuzumab treatment, we found that loss of signaling members downstream of phosphatidylinositol 3 kinase (PI3K) potentiated the growth inhibitory effects of trastuzumab. Loss of HER2 and HER3, as well as proteins involved in mitogenic and environmental stress pathways inhibited the proliferation of HER2+ cells only in the absence of trastuzumab, suggesting that these pathways are inhibited by trastuzumab treatment. Loss of essential G2/M cell cycle mediators or proteins involved in vesicle organization exerted inhibitory effects on HER2+ cell growth that were unaffected by trastuzumab. Furthermore, the use of a sensitization index (SI) identified targeting the PI3K pathway to sensitize to trastuzumab treatment. Antagonism using the SI identified MYO3A, MYO3B and MPZL1 as antagonizers to trastuzumab treatment among HER2+ cell lines. Our results suggest that the dimerization partners of HER2 are important for determining the activation of downstream proliferation pathways. Understanding the complex layers of signaling triggered downstream of HER2 homodimers and heterodimers will facilitate the selection of better targets for combination therapies intended to treat HER2+ breast cancers. |
format | Online Article Text |
id | pubmed-4275559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-42755592015-01-05 Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy Lapin, V Shirdel, E A Wei, X Mason, J M Jurisica, I Mak, T W Oncogenesis Original Article Understanding the signaling differences that distinguish human HER2-amplified (HER2-positive (HER2+)) breast cancers from other breast cancer subtypes may help to identify protein drug targets for the specific treatment of HER2+ breast cancers. We performed two kinome-wide small interfering RNA (siRNA) screens on five HER2+ breast cancer cell lines, seven breast cancer cell lines in which HER2 was not amplified and two normal breast cell lines. To pinpoint the main kinases driving HER2 signaling, we performed a comprehensive siRNA screen that identified loss of the HER2/HER3 heterodimer as having the most prominent inhibitory effect on the growth of HER2+ breast cancer cells. In a second siRNA screen focused on identifying genes that could sensitize HER2+ cells to trastuzumab treatment, we found that loss of signaling members downstream of phosphatidylinositol 3 kinase (PI3K) potentiated the growth inhibitory effects of trastuzumab. Loss of HER2 and HER3, as well as proteins involved in mitogenic and environmental stress pathways inhibited the proliferation of HER2+ cells only in the absence of trastuzumab, suggesting that these pathways are inhibited by trastuzumab treatment. Loss of essential G2/M cell cycle mediators or proteins involved in vesicle organization exerted inhibitory effects on HER2+ cell growth that were unaffected by trastuzumab. Furthermore, the use of a sensitization index (SI) identified targeting the PI3K pathway to sensitize to trastuzumab treatment. Antagonism using the SI identified MYO3A, MYO3B and MPZL1 as antagonizers to trastuzumab treatment among HER2+ cell lines. Our results suggest that the dimerization partners of HER2 are important for determining the activation of downstream proliferation pathways. Understanding the complex layers of signaling triggered downstream of HER2 homodimers and heterodimers will facilitate the selection of better targets for combination therapies intended to treat HER2+ breast cancers. Nature Publishing Group 2014-12 2014-12-15 /pmc/articles/PMC4275559/ /pubmed/25500906 http://dx.doi.org/10.1038/oncsis.2014.45 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Original Article Lapin, V Shirdel, E A Wei, X Mason, J M Jurisica, I Mak, T W Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title | Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title_full | Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title_fullStr | Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title_full_unstemmed | Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title_short | Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
title_sort | kinome-wide screening of her2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275559/ https://www.ncbi.nlm.nih.gov/pubmed/25500906 http://dx.doi.org/10.1038/oncsis.2014.45 |
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