Gene expression changes during acquired resistance to tamoxifen; a preclinical model of post-menopausal breast cancer
Bibliographic record
Abstract
3147 Background: Most metastatic breast cancers initially respond to hormonal treatment but all become resistant to these treatments over time. The genetic events that occur during acquired resistance are unknown. To examine the gene expression changes during acquired hormonal resistance, we used a model that mimics ER positive breast cancers in the post-menopausal setting with the tumors responsive to both Tamoxifen (TAM) and aromatase inhibitors. Tumors were analyzed with high density cDNA microarrays to identify genes associated with TAM resistance. Methods: Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumor xenografts in female ovariectomized athymic nude mice in which an androstenedione supplement was converted to estrogen to stimulate tumor growth. When tumor volume was approximately 300 mm3, the animals were grouped (4 groups, each with n=20) for continued supplementation with androstenedione (Δ4A) only (control), Letrozole (an aromatase inhibitor) 10 μg/day + Δ4A, TAM 100 μg/day + Δ4A, or vehicle. Tumors were then retrieved at various time points during the development of hormone resistance. Tumor RNA samples were compared to reference RNA from Stratagene and incubated with 14K microarrays (Array-Ready Oligo Set, Qiagen). Expression results were analyzed with Genespring 6.1 (Silicon Genetics). Results: We have identified 15 TAM-resistant associated genes that are over-expressed by at least 2-fold, after controlling for genes associated with house-keeping function (vehicle and short term control), proliferation (freely growing tumors without TAM), and TAM inducible genes. They include; cystatin A, TGFbeta1-induced anti-apoptotic factor, cadherin1 E-cadherin, Snf2-related CBP activator protein, and chromatin-remodelling genes. At the meeting we will also present data on the expression changes seen in the Her-regulin family, cyclin family and MAP kinase genes during acquired TAM resistance. Patient biopsies are currently being collected and analyzed to validate these observations. Conclusions: Chromatin remodeling genes are over-expressed in acquired TAM-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".