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Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways

The Neuregulins (NRGs) are growth factors that bind and activate ErbB/HER receptor tyrosine kinases. Some reports have described an interplay between this ligand–receptor system and hormonal receptors in breast cancer. However, the mechanisms by which NRGs regulate hormonal receptor signaling have n...

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Autores principales: Almaraz Postigo, Sheila, Montero, Juan Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805957/
https://www.ncbi.nlm.nih.gov/pubmed/36511917
http://dx.doi.org/10.1042/CS20220472
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author Almaraz Postigo, Sheila
Montero, Juan Carlos
author_facet Almaraz Postigo, Sheila
Montero, Juan Carlos
author_sort Almaraz Postigo, Sheila
collection PubMed
description The Neuregulins (NRGs) are growth factors that bind and activate ErbB/HER receptor tyrosine kinases. Some reports have described an interplay between this ligand–receptor system and hormonal receptors in breast cancer. However, the mechanisms by which NRGs regulate hormonal receptor signaling have not been sufficiently described. Here, we show that in breast cancer cells the activation of NRG receptors down-regulated ERα through a double mechanism that included post-transcriptional and transcriptional effects. This regulation required the concerted participation of three signaling routes: the PI3K/AKT/mTOR, ERK1/2, and ERK5 pathways. Moreover, these three routes were also involved in the phosphorylation of ERα at serines 118 and 167, two residues implicated in resistance to endocrine therapies. On the other hand, NRGs conferred resistance to fulvestrant in breast cancer cells and this resistance could be reversed when the three pathways activated by NRGs were simultaneously inhibited. Our results indicate that estrogen receptor-positive (ER+) breast tumors that can have access to NRGs may be resistant to fulvestrant. This resistance could be overcome if strategies to target the three main pathways involved in the interplay between NRG receptors and ERα could be developed.
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spelling pubmed-98059572023-01-09 Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways Almaraz Postigo, Sheila Montero, Juan Carlos Clin Sci (Lond) Cancer The Neuregulins (NRGs) are growth factors that bind and activate ErbB/HER receptor tyrosine kinases. Some reports have described an interplay between this ligand–receptor system and hormonal receptors in breast cancer. However, the mechanisms by which NRGs regulate hormonal receptor signaling have not been sufficiently described. Here, we show that in breast cancer cells the activation of NRG receptors down-regulated ERα through a double mechanism that included post-transcriptional and transcriptional effects. This regulation required the concerted participation of three signaling routes: the PI3K/AKT/mTOR, ERK1/2, and ERK5 pathways. Moreover, these three routes were also involved in the phosphorylation of ERα at serines 118 and 167, two residues implicated in resistance to endocrine therapies. On the other hand, NRGs conferred resistance to fulvestrant in breast cancer cells and this resistance could be reversed when the three pathways activated by NRGs were simultaneously inhibited. Our results indicate that estrogen receptor-positive (ER+) breast tumors that can have access to NRGs may be resistant to fulvestrant. This resistance could be overcome if strategies to target the three main pathways involved in the interplay between NRG receptors and ERα could be developed. Portland Press Ltd. 2023-01 2022-12-23 /pmc/articles/PMC9805957/ /pubmed/36511917 http://dx.doi.org/10.1042/CS20220472 Text en © 2022 The Author(s). https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Cancer
Almaraz Postigo, Sheila
Montero, Juan Carlos
Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title_full Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title_fullStr Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title_full_unstemmed Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title_short Neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
title_sort neuregulin modulates hormone receptor levels in breast cancer through concerted action on multiple signaling pathways
topic Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9805957/
https://www.ncbi.nlm.nih.gov/pubmed/36511917
http://dx.doi.org/10.1042/CS20220472
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