FAS death receptor: A breast cancer subtype-specific radiation response biomarker and potential therapeutic target
Journal
Radiation Research
Journal Volume
184
Journal Issue
5
Pages
456-469
Date Issued
2015
Author(s)
Horton J.K.
Siamakpour-Reihani S.
Lee C.-T.
Zhou Y.
Chen W.
Geradts J.
Fels D.R.
Hoang P.
Ashcraft K.A.
Groth J.
Dewhirst M.W.
Chi J.-T.A.
Abstract
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. ? 2015 by Radiation Research Society.
SDGs
Other Subjects
Fas ligand; Fas antigen; transcriptome; tumor marker; adult; Article; breast cancer; breast cancer cell line; cancer radiotherapy; clinical article; controlled clinical trial; controlled study; female; gene expression; human; human cell; intraductal carcinoma; invasive carcinoma; maximum tolerated dose; microarray analysis; phase 1 clinical trial; preoperative radiotherapy; priority journal; radiation dose; radiation exposure; radiation response; radiosensitivity; reverse transcription polymerase chain reaction; Breast Neoplasms; clinical trial; DNA microarray; genetics; metabolism; middle aged; molecularly targeted therapy; pathology; phenotype; protein transport; radiation response; radiation tolerance; transcription initiation; tumor cell line; tumor suppressor gene; Antigens, CD95; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Female; Genes, p53; Humans; Middle Aged; Molecular Targeted Therapy; Oligonucleotide Array Sequence Analysis; Phenotype; Protein Transport; Radiation Tolerance; Transcriptional Activation; Transcriptome
Publisher
Radiation Research Society
Type
journal article