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FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.

Publication ,  Journal Article
Horton, JK; Siamakpour-Reihani, S; Lee, C-T; Zhou, Y; Chen, W; Geradts, J; Fels, DR; Hoang, P; Ashcraft, KA; Groth, J; Kung, H-N; Dewhirst, MW ...
Published in: Radiat Res
November 2015

Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in radioresistant basal cell lines. Our findings suggest that cell-type-specific, radiation-induced FAS contributes to subtype-specific breast cancer radiation response and that activation of FAS pathways may be exploited for biologically tailored radiotherapy.

Duke Scholars

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Published In

Radiat Res

DOI

EISSN

1938-5404

Publication Date

November 2015

Volume

184

Issue

5

Start / End Page

456 / 469

Location

United States

Related Subject Headings

  • fas Receptor
  • Transcriptome
  • Transcriptional Activation
  • Radiation Tolerance
  • Protein Transport
  • Phenotype
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Molecular Targeted Therapy
  • Middle Aged
 

Citation

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Horton, J. K., Siamakpour-Reihani, S., Lee, C.-T., Zhou, Y., Chen, W., Geradts, J., … Chi, J.-T. (2015). FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target. Radiat Res, 184(5), 456–469. https://doi.org/10.1667/RR14089.1
Horton, Janet K., Sharareh Siamakpour-Reihani, Chen-Ting Lee, Ying Zhou, Wei Chen, Joseph Geradts, Diane R. Fels, et al. “FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.Radiat Res 184, no. 5 (November 2015): 456–69. https://doi.org/10.1667/RR14089.1.
Horton JK, Siamakpour-Reihani S, Lee C-T, Zhou Y, Chen W, Geradts J, et al. FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target. Radiat Res. 2015 Nov;184(5):456–69.
Horton, Janet K., et al. “FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target.Radiat Res, vol. 184, no. 5, Nov. 2015, pp. 456–69. Pubmed, doi:10.1667/RR14089.1.
Horton JK, Siamakpour-Reihani S, Lee C-T, Zhou Y, Chen W, Geradts J, Fels DR, Hoang P, Ashcraft KA, Groth J, Kung H-N, Dewhirst MW, Chi J-TA. FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target. Radiat Res. 2015 Nov;184(5):456–469.

Published In

Radiat Res

DOI

EISSN

1938-5404

Publication Date

November 2015

Volume

184

Issue

5

Start / End Page

456 / 469

Location

United States

Related Subject Headings

  • fas Receptor
  • Transcriptome
  • Transcriptional Activation
  • Radiation Tolerance
  • Protein Transport
  • Phenotype
  • Oncology & Carcinogenesis
  • Oligonucleotide Array Sequence Analysis
  • Molecular Targeted Therapy
  • Middle Aged