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Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy

Triple Negative Breast Cancer (TNBC) is characterized as a lack of expression of the hormonal receptors, estrogen and progesterone, and Human epidermal growth factor receptor 2 (HER2) and as such is unresponsive to current targeted therapy. Resistance of breast cancers to treatment is thought to be...

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Autores principales: Arnold, Kimberly M., Flynn, Nicole J., Sims-Mourtada, Jennifer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305183/
https://www.ncbi.nlm.nih.gov/pubmed/28203638
http://dx.doi.org/10.17140/CSMMOJ-2-112
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author Arnold, Kimberly M.
Flynn, Nicole J.
Sims-Mourtada, Jennifer
author_facet Arnold, Kimberly M.
Flynn, Nicole J.
Sims-Mourtada, Jennifer
author_sort Arnold, Kimberly M.
collection PubMed
description Triple Negative Breast Cancer (TNBC) is characterized as a lack of expression of the hormonal receptors, estrogen and progesterone, and Human epidermal growth factor receptor 2 (HER2) and as such is unresponsive to current targeted therapy. Resistance of breast cancers to treatment is thought to be due to a sub-population of tumor cells called Breast Cancer Stem Cells (BCSCs) and contributes to poor prognosis and increased risk of recurrence. Previously, we have shown that hedgehog activation is induced by chemotherapy and promotes expansion of a stem-like population in breast cancer cell lines. In addition, chemotherapy can induce an inflammatory response and inflammatory factors can lead to activation of Hedgehog (HH) at sites of tissue injury. Therefore, we wanted to investigate how chemotherapy altered hedgehog signaling and correlated with the release of inflammatory cytokines in a mouse model of breast cancer. Patient derived triple negative breast tumor bearing mice were treated with weekly doses of docetaxel. Following treatment, tumor volume decreased reaching a nadir around 15 days after the start of treatment and increased back to pre-treatment size 35-39 days post treatment. Immunohistochemical staining of mice tumors revealed that Sonic hedgehog and nuclear Gli-1 expression transiently increased following docetaxel treatment, reached peak expression at day 8, and subsequently decreased to almost pre-treatment levels following regrowth of the tumor. Similarly, Interleukin 6 (IL-6) and Interleukin 8 (IL-8) expression transiently increased, peaked around day 8, and decreased upon tumor regrowth, however, remained above pre-treatment levels. Expression of the stem cell marker ALDH1A3 proceeded activation of hedgehog signaling and expression of inflammatory cytokines, increasing around day 15 post treatment and continued to be elevated during tumor regrowth. Thus, chemotherapy treatment resulted in activation of the hedgehog pathway and release of inflammatory cytokines leading to long-term expansion of ALDH1A3 positive stem cells, which can contribute to the regrowth of the tumor and promote resistance to treatment.
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spelling pubmed-53051832017-02-13 Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy Arnold, Kimberly M. Flynn, Nicole J. Sims-Mourtada, Jennifer Cancer Stud Mol Med Article Triple Negative Breast Cancer (TNBC) is characterized as a lack of expression of the hormonal receptors, estrogen and progesterone, and Human epidermal growth factor receptor 2 (HER2) and as such is unresponsive to current targeted therapy. Resistance of breast cancers to treatment is thought to be due to a sub-population of tumor cells called Breast Cancer Stem Cells (BCSCs) and contributes to poor prognosis and increased risk of recurrence. Previously, we have shown that hedgehog activation is induced by chemotherapy and promotes expansion of a stem-like population in breast cancer cell lines. In addition, chemotherapy can induce an inflammatory response and inflammatory factors can lead to activation of Hedgehog (HH) at sites of tissue injury. Therefore, we wanted to investigate how chemotherapy altered hedgehog signaling and correlated with the release of inflammatory cytokines in a mouse model of breast cancer. Patient derived triple negative breast tumor bearing mice were treated with weekly doses of docetaxel. Following treatment, tumor volume decreased reaching a nadir around 15 days after the start of treatment and increased back to pre-treatment size 35-39 days post treatment. Immunohistochemical staining of mice tumors revealed that Sonic hedgehog and nuclear Gli-1 expression transiently increased following docetaxel treatment, reached peak expression at day 8, and subsequently decreased to almost pre-treatment levels following regrowth of the tumor. Similarly, Interleukin 6 (IL-6) and Interleukin 8 (IL-8) expression transiently increased, peaked around day 8, and decreased upon tumor regrowth, however, remained above pre-treatment levels. Expression of the stem cell marker ALDH1A3 proceeded activation of hedgehog signaling and expression of inflammatory cytokines, increasing around day 15 post treatment and continued to be elevated during tumor regrowth. Thus, chemotherapy treatment resulted in activation of the hedgehog pathway and release of inflammatory cytokines leading to long-term expansion of ALDH1A3 positive stem cells, which can contribute to the regrowth of the tumor and promote resistance to treatment. 2015-12-07 2015 /pmc/articles/PMC5305183/ /pubmed/28203638 http://dx.doi.org/10.17140/CSMMOJ-2-112 Text en http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Arnold, Kimberly M.
Flynn, Nicole J.
Sims-Mourtada, Jennifer
Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title_full Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title_fullStr Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title_full_unstemmed Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title_short Activation of Inflammatory Responses Correlate With Hedgehog Activation and Precede Expansion of Cancer Stem-Like Cells in an Animal Model of Residual Triple Negative Breast Cancer after Neoadjuvant Chemotherapy
title_sort activation of inflammatory responses correlate with hedgehog activation and precede expansion of cancer stem-like cells in an animal model of residual triple negative breast cancer after neoadjuvant chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305183/
https://www.ncbi.nlm.nih.gov/pubmed/28203638
http://dx.doi.org/10.17140/CSMMOJ-2-112
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