Abstract 3573: 17β-estradiol enhances hPygopus2 expression via ERα-SP1 promoter complexes.
Bibliographic record
Abstract
Abstract Background: The chromatin remodeling protein Human Pygopus2 (hPYGO2) is widely overexpressed in, and required for the proliferation of several cancer cell lines derived from a variety of tumors. Because of the requirement of hPYGO2 for the G1/S cell cycle transition, its cell cycle dependent expression and its regulation by the Retinoblastoma protein in breast cancer (BC) cells, we hypothesized a fundamental link to the cell cycle. Thus, due to their predominant role in BC, we tested if 17β-estradiol (E2) would cause upregulation of hPYGO2 through Estrogen receptor alpha-SP1 transcription factor (ERα-SP1) promoter complexes.Methods: Eight ERα positive (ER+) and negative (ER-) BC cell lines were grown in low serum conditions and treated with ERα agonists and/or antagonists. mRNA levels were analyzed by Q-PCR and protein by immunoblot. ERα and SP1 promoter binding sites and DNA binding domains were functionally inactivated by site-directed mutagenesis. ERα and SP1 occupancy at the hPYGO2 promoter after treatment with various activators/inhibitors was analyzed by chromatin immunoprecipitation assays. Cell cycle progression was assessed by flow cytometry.Results: hPygopus2 mRNA and protein levels were higher in ER+ BC cells relative to ER- cells. ERα agonists induced, while antagonists inhibited, hPygopus2 mRNA and protein expression. ERα and SP1 occupancy at the hPYGO2 promoter required intact promoter binding sites and functional DNA binding domains. E2 increased, while Fulvestrant decreased, ERα binding to the hPYGO2 promoter while having no effect on SP1 binding. SP1 directed siRNA reduced SP1 occupancy at the hPYGO2 promoter and decreased hPygopus2 mRNA and protein expression in both ER+ and ER- cells. Treatment with betulinic acid, an SP1 inhibitor, resulted in cell cycle arrest in ER- BC cell lines.Conclusion: Our findings indicate that ERα and SP1 regulate hPygopus2 expression via promoter binding and that SP1 continues to play a role in hPYGO2 regulation in ER- cells, thereby revealing the potential efficacy of betulinic acid as a treatment for endocrine-disruptor resistant BC. Citation Format: Youlian R. Tzenov, Phillip G. Andrews, Kenneth R. Kao. 17β-estradiol enhances hPygopus2 expression via ERα-SP1 promoter complexes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3573. doi:10.1158/1538-7445.AM2013-3573
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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 | 0.000 | 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) | 0.004 | 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".