Estrogen regulation of anti-apoptotic Bcl-2 family member Mcl-1 expression in breast cancer
Bibliographic record
Abstract
INTRODUCTION Estrogen is implicated as an important factor in stimulating breast cancer cell proliferation, and presence of estrogen receptor (ER) is an indication of a good prognosis in breast cancer patients. Mcl-1 is an anti-apoptotic Bcl-2 family member that is often overexpressed in breast tumors, correlating with poor survival. Estrogen has been previously shown to regulate Bcl-2 family members, leading to an evasion of apoptosis, however the role of estrogen in regulating Mcl-1 expression is unclear. I hypothesize that estrogen increases the expression of anti-apoptotic gene Mcl-1 through binding of ERα to a half estrogen response element (ERE) site within the promoter of Mcl-1 gene. This leads to increased Mcl-1 expression in breast cancer cells, ultimately contributing to an evasion of apoptosis. METHODS Four distinct breast cancer cell lines: MCF-7 and ZR-75, which both express ERα, and SKB-BR-3 and MDA-MB-231, which do not express ERα, to investigate the role of estrogen plays in regulating Mcl-1 expression. Cells were grown in serum-starved white media with charcoal-stripped FBS for five days prior to treatment with estrogen. Cells were treated with ERα antagonists Tamoxifen and Fulvestrant in combination with estrogen. Also, siRNA knockdown of ERα was performed and mRNA expression was evaluated. Chromatin immunoprecipitation (ChIP) was used to investigate if ERα binds to a specific ERE halfsite within the Mcl-1 promoter. To further validate this data, a streptavidin pull-down assay was performed using a biotinlabeled probe specific to this region. RESULTS In ERα positive cell lines, estrogen treatment increased Mcl-1 expression at both the protein and mRNA level. In two ERα negative cell lines, SK-BR-3 and MDA-MB-231, estrogen failed to increase in Mcl-1 protein expression. ERα antagonists decreased estrogen mediated Mcl-1 expression at both the protein and message level. Upon knockdown of ERα, Mcl-1 mRNA expression after estrogen treatment was also decreased. ChIP showed an enrichment of ERα to the Mcl-1 promoter at a region 3683 bp upstream of the translation start site containing a half ERE site. Streptavidin-pull down assay showed both ERα and transcription factor Sp1 bind to this region and mutation of the half ERE site eliminated this binding. CONCLUSIONS These results suggest that estrogen is involved in regulating Mcl-1 expression specifically through a mechanism involving ERα. Ultimately, a better understanding of the role of estrogen in regulating Mcl-1 expression will determine whether Mcl-1 is a valid molecular target for breast cancer therapy.
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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) | 0.003 | 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 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".