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

Publication ,  Journal Article
Li, S; Payne, S; Wang, F; Claus, P; Su, Z; Groth, J; Geradts, J; de Ridder, G; Alvarez, R; Marcom, PK; Pizzo, SV; Bachelder, RE
Published in: Breast Cancer Res
July 4, 2015

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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Published In

Breast Cancer Res

DOI

EISSN

1465-542X

Publication Date

July 4, 2015

Volume

17

Issue

1

Start / End Page

91

Location

England

Related Subject Headings

  • Tumor Stem Cell Assay
  • Triple Negative Breast Neoplasms
  • Protein Transport
  • Oncology & Carcinogenesis
  • Humans
  • Gene Expression
  • Fibroblast Growth Factor 2
  • Female
  • Drug Resistance, Neoplasm
  • DNA-Activated Protein Kinase
 

Citation

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Li, S., Payne, S., Wang, F., Claus, P., Su, Z., Groth, J., … Bachelder, R. E. (2015). Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance. Breast Cancer Res, 17(1), 91. https://doi.org/10.1186/s13058-015-0590-3
Li, Shenduo, Sturgis Payne, Fang Wang, Peter Claus, Zuowei Su, Jeffrey Groth, Joseph Geradts, et al. “Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance.Breast Cancer Res 17, no. 1 (July 4, 2015): 91. https://doi.org/10.1186/s13058-015-0590-3.
Li S, Payne S, Wang F, Claus P, Su Z, Groth J, et al. Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance. Breast Cancer Res. 2015 Jul 4;17(1):91.
Li, Shenduo, et al. “Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance.Breast Cancer Res, vol. 17, no. 1, July 2015, p. 91. Pubmed, doi:10.1186/s13058-015-0590-3.
Li S, Payne S, Wang F, Claus P, Su Z, Groth J, Geradts J, de Ridder G, Alvarez R, Marcom PK, Pizzo SV, Bachelder RE. Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance. Breast Cancer Res. 2015 Jul 4;17(1):91.

Published In

Breast Cancer Res

DOI

EISSN

1465-542X

Publication Date

July 4, 2015

Volume

17

Issue

1

Start / End Page

91

Location

England

Related Subject Headings

  • Tumor Stem Cell Assay
  • Triple Negative Breast Neoplasms
  • Protein Transport
  • Oncology & Carcinogenesis
  • Humans
  • Gene Expression
  • Fibroblast Growth Factor 2
  • Female
  • Drug Resistance, Neoplasm
  • DNA-Activated Protein Kinase