Molecular interactions between insulin-like growth factor signal transduction and retinoids in breast cancer cells
Bibliographic record
Abstract
Numerous groups, including ours, have found that retinoids potently inhibit the growth of breast cancer cells, but the mechanisms by which growth regulation is achieved remains unclear. Although several of the effects of retinoids in breast cancer have been linked to the insulin-like growth factor (IGF) system, their effects on key signaling molecules in the IGF type-I receptor (IGF-IR) pathway have not been well characterized. This thesis project examined the hypothesis that retinoids mediate their growth inhibitory effects by targeting specific members of the IGF-IR signal transduction pathway. Although we did not observe regulation of IGF-IR itself, we found that all-trans retinoic acid (RA)-mediated growth inhibition is associated with a selective reduction in insulin receptor substrate 1 (IRS-1) protein and activity levels. We also present evidence that decreasing IRS-1 levels results in the selective down-regulation of the PI 3-kinase/AKT pathway in RA-treated MCF-7 cells. The relevance of IRS-1 regulation to the growth inhibitory action of RA is supported by the results showing that forced expression of IRS-1 abrogates the ability of RA to significantly inhibit MCF-7 cell growth. Several studies have highlighted the importance of IRS-1 in breast cancer pathogenesis. High levels of IRS-1 in human breast tumors correlate with increased disease recurrence and constitutive IRS-1 signaling exists in breast tumors. This suggests that we may develop molecular strategies targeting IRS-1 by understanding the mechanisms controlling its expression and turnover. Since RA decreased IRS-1 protein levels without altering mRNA levels, we examined the hypothesis that RA-mediated regulation of IRS-1 levels was at the posttranslational level. Two proteasome inhibitors rescue the RA-mediated degradation of IRS-1, and RA increases the ubiquitination of IRS-1. We also found that RA increases the serine phosphorylation of IRS-1 and show that this occurs in a protein kinase C (PKC)-dependant manner, since PKC inhibitors block the RA-induced degradation and serine phosphorylation of IRS-1. We further demonstrate that RA activates PKC-delta in the sensitive, but not in the resistant cells, with a time course that is consistent with the RA-induced decrease of IRS-1. The involvement of PKC in the RA-mediated regulation of IRS-1 is supported by additional data showing that: (1) RA-activated PKC-delta phosphorylates IRS-1 in vitro, (2) PKC-delta and IRS-1 interact in RA-treated cells, and (3) mutation of three PKC-delta serine sites in IRS-1 to alanines results in no RA-induced in vitro phosphorylation of IRS-1. Having identified IRS-1 as a novel target of RA and showing that RA regulates this protein via a mechanism involving the ubiquitin-proteasome pathway has contributed to an enhanced understanding of the effect of retinoids in human breast cancer cells.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".