Abstract 4023: ARID1A is a candidate tumor suppressor gene in breast cancer
Bibliographic record
Abstract
Abstract Tumor suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. Typically but not always, tumors neutralize both alleles of TSGs by deleting one copy and mutating the other. One molecular strategy to discover potential tumor suppressor gene candidates involves the “re-expression” of RNA transcripts containing nonsense mutations by inhibition of the nonsense-mediated RNA decay (NMD) process. Combining NMD inhibition with array CGH has lead to the genome-wide identification of genes with biallelic inactivation (involving nonsense mutations on one allele and loss of the second allele) in prostate cancer cell lines and identified EphB2 as a novel candidate TSG in prostate cancer. Using such a strategy in 5 breast cancer cell lines, we identified ARID1A as a NMD target in the T47D breast cancer cell line. ARID1A encodes a human homologue of yeast SWI1, which contains a DNA-binding motif (AT-rich interactive domain, ARID) and is an integral member of the hSWI/SNF complex, an ATP-dependent chromatin-remodeling multiple-subunit enzyme. Mutations in the ARID1A gene were recently reported to be present in 50% of clear cell tumors of the ovary. We found the ARID1A gene contains a nonsense mutation in exon 9, which introduces a premature stop codon, changing Q944 to a stop codon in the T47D breast cancer cell line. Although we did not find any somatic mutations in breast tumors, we show that low ARID1A RNA expression or low ARID1A nuclear protein expression is associated with more aggressive breast cancer phenotypes in 2 independent cohorts of over 200 breast cancers each. We also found that low or absent ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the breast cancer cell line in which it is mutated results in significant inhibition of colony formation in soft agar. These results suggest that the ARID1A gene may be a candidate tumor suppressor gene in breast cancer, and that it warrants further investigation as potential diagnostic and therapeutic marker in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2011-4023
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".