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Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors

Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment fail...

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Autores principales: Yeh, Elizabeth S., Abt, Melissa A., Hill, Elizabeth G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342830/
https://www.ncbi.nlm.nih.gov/pubmed/25515931
http://dx.doi.org/10.1007/s10549-014-3227-9
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author Yeh, Elizabeth S.
Abt, Melissa A.
Hill, Elizabeth G.
author_facet Yeh, Elizabeth S.
Abt, Melissa A.
Hill, Elizabeth G.
author_sort Yeh, Elizabeth S.
collection PubMed
description Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial. Moreover, autophagy is mechanistically linked through signaling crosstalk to apoptotic pathways, where activation of one process impacts the other. Therefore, understanding the molecular mechanisms that control these processes may uncover novel areas of therapeutic intervention to combat or prevent resistance in breast cancer. We previously characterized the protein kinase HUNK as a breast cancer-promoting factor in HER2/neu-induced mammary tumor models, in which HUNK supported the survival of HER2/neu-positive tumor cells, likely through the regulation of apoptosis. Because significant crosstalk exists between apoptotic and autophagy proteins, we now examine if HUNK is also able to regulate cell survival through modulation of autophagy using HER2 inhibitor sensitive and resistant breast cancer models. Furthermore, we investigate whether inhibiting HUNK impairs in vivo tumor growth that is initiated by HER2 inhibitor-resistant breast cancer cells. Our findings indicate that therapeutically targeting HUNK is a potential strategy for overcoming resistance and that resistant breast cancer cells maintain HUNK expression to drive tumorigenesis, an observation that is consistent with a pro-survival role for this kinase. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-014-3227-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-43428302015-03-04 Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors Yeh, Elizabeth S. Abt, Melissa A. Hill, Elizabeth G. Breast Cancer Res Treat Preclinical Study Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial. Moreover, autophagy is mechanistically linked through signaling crosstalk to apoptotic pathways, where activation of one process impacts the other. Therefore, understanding the molecular mechanisms that control these processes may uncover novel areas of therapeutic intervention to combat or prevent resistance in breast cancer. We previously characterized the protein kinase HUNK as a breast cancer-promoting factor in HER2/neu-induced mammary tumor models, in which HUNK supported the survival of HER2/neu-positive tumor cells, likely through the regulation of apoptosis. Because significant crosstalk exists between apoptotic and autophagy proteins, we now examine if HUNK is also able to regulate cell survival through modulation of autophagy using HER2 inhibitor sensitive and resistant breast cancer models. Furthermore, we investigate whether inhibiting HUNK impairs in vivo tumor growth that is initiated by HER2 inhibitor-resistant breast cancer cells. Our findings indicate that therapeutically targeting HUNK is a potential strategy for overcoming resistance and that resistant breast cancer cells maintain HUNK expression to drive tumorigenesis, an observation that is consistent with a pro-survival role for this kinase. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-014-3227-9) contains supplementary material, which is available to authorized users. Springer US 2014-12-17 2015 /pmc/articles/PMC4342830/ /pubmed/25515931 http://dx.doi.org/10.1007/s10549-014-3227-9 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Preclinical Study
Yeh, Elizabeth S.
Abt, Melissa A.
Hill, Elizabeth G.
Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title_full Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title_fullStr Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title_full_unstemmed Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title_short Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors
title_sort regulation of cell survival by hunk mediates breast cancer resistance to her2 inhibitors
topic Preclinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342830/
https://www.ncbi.nlm.nih.gov/pubmed/25515931
http://dx.doi.org/10.1007/s10549-014-3227-9
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