Abstract P5-05-01: IGFBP-7 Reduces Growth of Xenografted Breast Tumors in Mice and Inhibits Breast Cancer Cell Proliferation and Migration through the MEK-ERK Pathway
Bibliographic record
Abstract
Abstract To identify genes correlated with breast tumorigenesis and eventual metastasis, gene expression profiles were generated using 28K whole genome microarrays. Gene expression profiles of primary breast tumors that grew and metastasized in the NOD/SCID mice were compared with other primary breast tumors that had different growth and metastatic potentials. Five hundred and eighty two genes were significantly differentially expressed by our statistical comparison criteria using the GeneSpring GX 7.3.1 software suite. In the metastatic set eight genes were selectively overexpressed (YB1, MMP7, MMP9, RAB5A, RABGDIB, EPHRB3, WNT2B, CSF1R) and 12 were selectively underexpressed (IGFBP7, GATA3, CST5, CDK6, SERBP1, MGP, TGF1L4, ESE3, ELF3, EDNRB, HECTD1, TINP1). In the present study we focused on the IGFBP-7 gene product which was found to be inversely correlated with disease progression in breast cancer. To further investigate the role of IGFBP-7 in breast tumor suppression, it was overexpressed in the triple negative MDA-MB-468 human breast cancer line. Ectopic overexpression of IGFBP-7 clearly reduced the growth of the MDA-MB-468/IGFBP-7 cells compared to the parental MDA-MB-468 cells. Ectopic overexpression or addition of rIGFBP-7 to breast cancer cell lines in vitro clearly reduced the growth of several breast cancer cell lines and resulted in phenotypic changes characterized by cell aggregation. Investigation of downstream signalling pathways affected by IGFBP-7 revealed that addition of IGFBP-7 to a triple negative breast cancer cell line not only inhibited phosphorylation of ERK-1/2 but also increased expression of the cyclin-dependent kinase inhibitor 1, p21. Similar IGFBP-7 treatment of an ER+ breast cancer line resulted not only in inhibition of ERK-1/2 phosphorylation, but also AKT phosphorylation, suggesting that IGFBP-7 may affect multiple pathways in hormone responsive breast cancer cell lines. IGFBP-7 protein is processed into a shorter form by matriptase. Breast cancer cell lines which were unable to process IGFBP-7 into the shorter form were unaffected by IGFBP-7 mediated growth inhibition, suggesting that cleaved IGFBP-7 may be required for growth inhibitory effects. When injected subcutaneously into NOD/SCID mice, the increased expression of IGFBP-7 in the MDA-MB-468/IGFBP-7 cells reduced the rate of tumor growth in comparison to the parental MDA-MB-468 cells. Furthermore, injection of rIGFBP-7 protein at the tumor site into breast cancer xenografted NOD/SCID mice also resulted in significant tumor growth reduction. These results suggest that the growth of breast cancer could be prevented by the forced expression of IGFBP-7 protein. Work in progress will further uncover the mechanism of IGFBP-7-mediated inhibition on signalling pathways, as well as differentiate the impact of both full length and cleaved IGFBP-7 protein on breast tumor inhibition. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-01.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".