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Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells
Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant therapy for estrogen receptor alpha (ERα)-positive breast cancer. However, the effectiveness of this drug is limited due to the development of resistance. The Hedgehog (HH) signaling pathway is critical in embryonic de...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342103/ https://www.ncbi.nlm.nih.gov/pubmed/27689403 http://dx.doi.org/10.18632/oncotarget.12259 |
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author | Diao, Yumei Azatyan, Ani Rahman, Mohammed Ferdous-Ur Zhao, Chunyan Zhu, Jian Dahlman-Wright, Karin Zaphiropoulos, Peter G. |
author_facet | Diao, Yumei Azatyan, Ani Rahman, Mohammed Ferdous-Ur Zhao, Chunyan Zhu, Jian Dahlman-Wright, Karin Zaphiropoulos, Peter G. |
author_sort | Diao, Yumei |
collection | PubMed |
description | Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant therapy for estrogen receptor alpha (ERα)-positive breast cancer. However, the effectiveness of this drug is limited due to the development of resistance. The Hedgehog (HH) signaling pathway is critical in embryonic development, and aberrant activation of this transduction cascade is linked to various malignancies. However, it remains unclear whether HH signaling is activated in human breast cancer and related to tamoxifen resistance. Deciphering how this pathway may be involved in breast cancer is a crucial step towards the establishment of targeted combinatorial treatments for this disease. Here, we show that the expression of the HH signaling effector protein GLI1 is higher in tamoxifen resistant compared to sensitive cells. Tamoxifen resistant cells have stronger ERα transcriptional activity relative to sensitive cells, even though the ERα expression is similar in both cell types. Knockdown of GLI1 attenuates cell proliferation and reduces ERα transcriptional activity in both sensitive and resistant cells, irrespective of estrogen stimulation. Combinatorial treatment of tamoxifen and the GLI antagonist GANT61 further suppresses the growth of sensitive and resistant cells relative to administration of only tamoxifen, and this was irrespective of estrogen stimulation. Moreover, a positive correlation between GLI1 and ERα expression was identified in breast cancer samples. Additionally, high GLI1 expression predicted worse distant metastasis-free survival in breast cancer patients. These data suggest that the HH pathway may be a new candidate for therapeutic targeting and prognosis in ERα-positive breast cancer. |
format | Online Article Text |
id | pubmed-5342103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53421032017-03-24 Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells Diao, Yumei Azatyan, Ani Rahman, Mohammed Ferdous-Ur Zhao, Chunyan Zhu, Jian Dahlman-Wright, Karin Zaphiropoulos, Peter G. Oncotarget Research Paper Anti-estrogen treatment, exemplified by tamoxifen, is a well-established adjuvant therapy for estrogen receptor alpha (ERα)-positive breast cancer. However, the effectiveness of this drug is limited due to the development of resistance. The Hedgehog (HH) signaling pathway is critical in embryonic development, and aberrant activation of this transduction cascade is linked to various malignancies. However, it remains unclear whether HH signaling is activated in human breast cancer and related to tamoxifen resistance. Deciphering how this pathway may be involved in breast cancer is a crucial step towards the establishment of targeted combinatorial treatments for this disease. Here, we show that the expression of the HH signaling effector protein GLI1 is higher in tamoxifen resistant compared to sensitive cells. Tamoxifen resistant cells have stronger ERα transcriptional activity relative to sensitive cells, even though the ERα expression is similar in both cell types. Knockdown of GLI1 attenuates cell proliferation and reduces ERα transcriptional activity in both sensitive and resistant cells, irrespective of estrogen stimulation. Combinatorial treatment of tamoxifen and the GLI antagonist GANT61 further suppresses the growth of sensitive and resistant cells relative to administration of only tamoxifen, and this was irrespective of estrogen stimulation. Moreover, a positive correlation between GLI1 and ERα expression was identified in breast cancer samples. Additionally, high GLI1 expression predicted worse distant metastasis-free survival in breast cancer patients. These data suggest that the HH pathway may be a new candidate for therapeutic targeting and prognosis in ERα-positive breast cancer. Impact Journals LLC 2016-09-26 /pmc/articles/PMC5342103/ /pubmed/27689403 http://dx.doi.org/10.18632/oncotarget.12259 Text en Copyright: © 2016 Diao et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Diao, Yumei Azatyan, Ani Rahman, Mohammed Ferdous-Ur Zhao, Chunyan Zhu, Jian Dahlman-Wright, Karin Zaphiropoulos, Peter G. Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title | Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title_full | Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title_fullStr | Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title_full_unstemmed | Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title_short | Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
title_sort | blockade of the hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342103/ https://www.ncbi.nlm.nih.gov/pubmed/27689403 http://dx.doi.org/10.18632/oncotarget.12259 |
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