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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.
This article was published in the following journal.
Name: Radiation research
Brain metastases from breast cancer are frequently managed with brain-directed radiation but the impact of subtype on intracranial recurrence patterns after radiation has not been well-described. We i...
Age and tumor subtype are prognostic factors for breast cancer survival, but it is unclear which matters the most. We used population-based data to address this question. We identified 21,384 women di...
Breast cancer risk is increased with current Menopausal Hormone Therapy (MHT) use, with higher risks reported for ER+ (Estrogen Receptor positive), and ER+/PR+ (Estrogen and Progesterone Receptor posi...
Approximately 3-5% of breast cancer patients are BRCA1- or BRCA2 germ-line mutation carriers. In this study we correlated the distribution of intrinsic molecular subtypes according to failure pattern ...
An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtyp...
Breast cancer is the most common female malignancy in the world, and the leading cause of cancer-associated mortalities among women. Hormone receptors (HR) including ER and PR are the main...
Very few patients with endocrine-resistant, hormone-receptor positive metastatic breast cancer respond to single agent immunotherapy. Responses to chemotherapy are usually of short duratio...
Basal like breast carcinoma is a Her2, estrogen receptor (ER) progesterone receptor (PR) negative breast cancer. It is notable for the high level of epidermal growth factor receptor (EGFR)...
The luminal subtype of breast cancer means hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+HER2-), which counted 60%-70% of breast cancer but achieve low p...
The goal of this clinical research study is to find the highest tolerable dose of M7824 (MSB0011359C) that can be given with radiation therapy to patients with estrogen and/or progesterone...
Abnormal accumulation of lymph in the arm, shoulder and breast area associated with surgical or radiation breast cancer treatments (e.g., MASTECTOMY).
A ectodysplasin receptor subtype that is specific for ECTODYSPLASIN A1. It signals via the specific signaling adaptor EDAR-ASSOCIATED DEATH DOMAIN PROTEIN. Loss of function of the edar receptor is associated with AUTOSOMAL RECESSIVE ANHIDROTIC ECTODERMAL DYSPLASIA and ECTODERMAL DYSPLASIA 3, ANHIDROTIC.
Metastatic breast cancer characterized by EDEMA and ERYTHEMA of the affected breast due to LYMPHATIC METASTASIS and eventual obstruction of LYMPHATIC VESSELS by the cancer cells.
A tumor necrosis factor receptor-associated factor that acts as a specific signaling adaptor protein for the EDAR RECEPTOR and plays an important role in ectodermal development. It binds to edar receptor via its C-terminal death domain region and to other specific TNF receptor-associated factors via its N-terminal domain. Loss of function of edar-associated death domain protein is associated with AUTOSOMAL RECESSIVE ANHIDROTIC ECTODERMAL DYSPLASIA.
A tumor necrosis factor receptor subtype found in a variety of tissues and on activated LYMPHOCYTES. It has specificity for FAS LIGAND and plays a role in regulation of peripheral immune responses and APOPTOSIS. Multiple isoforms of the protein exist due to multiple ALTERNATIVE SPLICING. The activated receptor signals via a conserved death domain that associates with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM. Mutations in the CD95 gene are associated with cases of autoimmune lymphoproliferative syndrome.
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A DNA microarray or biochip is a collection of microscopic DNA spots attached to a solid surface used to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome.