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Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance

INTRODUCTION: Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumo...

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Autores principales: Li, Shenduo, Payne, Sturgis, Wang, Fang, Claus, Peter, Su, Zuowei, Groth, Jeffrey, Geradts, Joseph, de Ridder, Gustaaf, Alvarez, Rebeca, Marcom, Paul Kelly, Pizzo, Salvatore V., Bachelder, Robin E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491247/
https://www.ncbi.nlm.nih.gov/pubmed/26141457
http://dx.doi.org/10.1186/s13058-015-0590-3
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author Li, Shenduo
Payne, Sturgis
Wang, Fang
Claus, Peter
Su, Zuowei
Groth, Jeffrey
Geradts, Joseph
de Ridder, Gustaaf
Alvarez, Rebeca
Marcom, Paul Kelly
Pizzo, Salvatore V.
Bachelder, Robin E.
author_facet Li, Shenduo
Payne, Sturgis
Wang, Fang
Claus, Peter
Su, Zuowei
Groth, Jeffrey
Geradts, Joseph
de Ridder, Gustaaf
Alvarez, Rebeca
Marcom, Paul Kelly
Pizzo, Salvatore V.
Bachelder, Robin E.
author_sort Li, Shenduo
collection PubMed
description INTRODUCTION: Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumor growth. Defining molecules responsible for TN breast cancer chemo-resistance is crucial for developing effective combination therapies blocking tumor recurrence. Historically, chemo-resistance studies have relied on long-term chemotherapy selection models that drive genetic mutations conferring cell survival. Other models suggest that tumors are heterogeneous, being composed of both chemo-sensitive and chemo-resistant tumor cell populations. We previously described a short-term chemotherapy treatment model that enriches for chemo-residual TN tumor cells. In the current work, we use this enrichment strategy to identify a novel determinant of TN breast cancer chemotherapy resistance [a nuclear isoform of basic fibroblast growth factor (bFGF)]. METHODS: Studies are conducted using our in vitro model of chemotherapy resistance. Short-term chemotherapy treatment enriches for a chemo-residual TN subpopulation that over time resumes proliferation. By western blotting and real-time polymerase chain reaction, we show that this chemotherapy-enriched tumor cell subpopulation expresses nuclear bFGF. The importance of bFGF for survival of these chemo-residual cells is interrogated using short hairpin knockdown strategies. DNA repair capability is assessed by comet assay. Immunohistochemistry (IHC) is used to determine nuclear bFGF expression in TN breast cancer cases pre- and post- neoadjuvant chemotherapy. RESULTS: TN tumor cells surviving short-term chemotherapy treatment express increased nuclear bFGF. bFGF knockdown reduces the number of chemo-residual TN tumor cells. Adding back a nuclear bFGF construct to bFGF knockdown cells restores their chemo-resistance. Nuclear bFGF-mediated chemo-resistance is associated with increased DNA-dependent protein kinase (DNA-PK) expression and accelerated DNA repair. In fifty-six percent of matched TN breast cancer cases, percent nuclear bFGF-positive tumor cells either increases or remains the same post- neoadjuvant chemotherapy treatment (compared to pre-treatment). These data indicate that in a subset of TN breast cancers, chemotherapy enriches for nuclear bFGF-expressing tumor cells. CONCLUSION: These studies identify nuclear bFGF as a protein in a subset of TN breast cancers that likely contributes to drug resistance following standard chemotherapy treatment.
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spelling pubmed-44912472015-07-05 Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance Li, Shenduo Payne, Sturgis Wang, Fang Claus, Peter Su, Zuowei Groth, Jeffrey Geradts, Joseph de Ridder, Gustaaf Alvarez, Rebeca Marcom, Paul Kelly Pizzo, Salvatore V. Bachelder, Robin E. Breast Cancer Res Research Article INTRODUCTION: Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumor growth. Defining molecules responsible for TN breast cancer chemo-resistance is crucial for developing effective combination therapies blocking tumor recurrence. Historically, chemo-resistance studies have relied on long-term chemotherapy selection models that drive genetic mutations conferring cell survival. Other models suggest that tumors are heterogeneous, being composed of both chemo-sensitive and chemo-resistant tumor cell populations. We previously described a short-term chemotherapy treatment model that enriches for chemo-residual TN tumor cells. In the current work, we use this enrichment strategy to identify a novel determinant of TN breast cancer chemotherapy resistance [a nuclear isoform of basic fibroblast growth factor (bFGF)]. METHODS: Studies are conducted using our in vitro model of chemotherapy resistance. Short-term chemotherapy treatment enriches for a chemo-residual TN subpopulation that over time resumes proliferation. By western blotting and real-time polymerase chain reaction, we show that this chemotherapy-enriched tumor cell subpopulation expresses nuclear bFGF. The importance of bFGF for survival of these chemo-residual cells is interrogated using short hairpin knockdown strategies. DNA repair capability is assessed by comet assay. Immunohistochemistry (IHC) is used to determine nuclear bFGF expression in TN breast cancer cases pre- and post- neoadjuvant chemotherapy. RESULTS: TN tumor cells surviving short-term chemotherapy treatment express increased nuclear bFGF. bFGF knockdown reduces the number of chemo-residual TN tumor cells. Adding back a nuclear bFGF construct to bFGF knockdown cells restores their chemo-resistance. Nuclear bFGF-mediated chemo-resistance is associated with increased DNA-dependent protein kinase (DNA-PK) expression and accelerated DNA repair. In fifty-six percent of matched TN breast cancer cases, percent nuclear bFGF-positive tumor cells either increases or remains the same post- neoadjuvant chemotherapy treatment (compared to pre-treatment). These data indicate that in a subset of TN breast cancers, chemotherapy enriches for nuclear bFGF-expressing tumor cells. CONCLUSION: These studies identify nuclear bFGF as a protein in a subset of TN breast cancers that likely contributes to drug resistance following standard chemotherapy treatment. BioMed Central 2015-07-04 2015 /pmc/articles/PMC4491247/ /pubmed/26141457 http://dx.doi.org/10.1186/s13058-015-0590-3 Text en © Li et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Li, Shenduo
Payne, Sturgis
Wang, Fang
Claus, Peter
Su, Zuowei
Groth, Jeffrey
Geradts, Joseph
de Ridder, Gustaaf
Alvarez, Rebeca
Marcom, Paul Kelly
Pizzo, Salvatore V.
Bachelder, Robin E.
Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title_full Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title_fullStr Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title_full_unstemmed Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title_short Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
title_sort nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491247/
https://www.ncbi.nlm.nih.gov/pubmed/26141457
http://dx.doi.org/10.1186/s13058-015-0590-3
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