Cullin-3 is a potential novel target for breast cancer chemoprevention and treatment
Bibliographic record
Abstract
13070 Background: Nrf2 is a master transcription factor regulating multiple phase II carcinogen-detoxifying enzymes. Modulating Nrf2 is a current chemoprevention strategy under investigation. Nrf2 levels are regulated by the Keap1, which functions as a substrate adaptor protein targeting Nrf2 to the Cullin-3 (Cul3)-dependent ubiquitin E3 ligase complex. Methods: We used RT-PCR and Western blot to measure the mRNA and protein levels of Nrf2, Keap1 and Cul3 in human breast cancer cell lines. SiRNA and retrovectors were used to construct stable Cul3 silenced breast cancer cell lines. Agilent DNA microarray analysis was used to study the Cul3-slienced cells. Results: We discovered that Nrf2 protein levels in both nucleus and cytoplasm are significantly decreased in all breast cancer cell lines examined compared to normal human mammary epithelial cells (HMEC). This was confirmed with IHC analysis in 8 out of 10 breast cancer specimens containing normal mammary tissues for comparison. Since RT-PCR showed no change in Nrf2 mRNA levels in the breast cancer cell lines, we examined the degradation pathway of Nrf2, and we found that Cul3 is significantly overexpressed in all three breast cancer cell lines studied compared to HMEC. Silencing Cul3 using siRNA results in restoration of Nrf2 protein level, along with multiple carcinogen-detoxifying enzymes, such as GCS. The Cul3 silenced cells showed remarkable growth retardation compared to the wild type MCF-7 cell line both in vitro and in vivo in a mouse mammary fat pad cancer xenograft model. Microarray analyses of Cul3 siRNA-slinced cells demonstrated upregulation of several detoxifying genes, altered cell cycle markers and several upregulated tumor suppressor genes. Conclusions: Nrf2 is significantly downregulated in breast cancer cells, which is related to the overexpression of Cul3, and may represent sensitivity of these cells to carcinogenic transformation. Knocking down Cul3 constitutively upregulates the Nrf2 as well as multiple carcinogen-detoxifying genes. Moreover, it significantly suppressess the proliferation of cancer cells in vitro and growth of xenograft tumors in vivo. These data suggest that Cul-3 is a potential new target for breast cancer chemoprevention and treatment. No significant financial relationships to disclose.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".