Abstract 5116: The calcium channel subunit CACNG4 plays a role in breast cancer metastasis.
Bibliographic record
Abstract
Abstract Introduction: Previously, we used aCGH to analyze genomic alterations in primary breast tumors with and without lymph node (LN) metastasis. A significant correlation was found between gain of chromosome 17q24 and LN metastasis. Selected genes including L-type calcium channel voltage dependent gamma subunit 4 (CACNG4) were further validated for increased protein expression in invasive breast tumors. CACNG4 is involved in calcium channel regulation in excitable cells of muscles and the brain. It is the only gamma subunit that also shows expression in non-excitable cells, such as glial and intestinal epithelial cells, suggestive of additional functions. It is over-expressed in glioblastoma multiforme cell lines resistant to EGFR inhibitors. Breast cancer gene expression datasets (NKI and IPC) identified an association of CACNG4 expression with LN metastasis and ER positivity. In the present study, we characterized CACNG4 in breast cancer with particular attention to its metastasis-related ability. Methodology: RNA interference was used for knockdown studies in cell lines followed by cell migration, invasion, aggregation and adhesion assays. Intracellular calcium influx in response to calcium channel agonists and antagonists was measured using the Fluo-4 calcium indicator dye. Results: CACNG4 showed variable expression across a panel of breast cancer cell lines. MCF10A (a non malignant cell line) does not express CACNG4, while it is highly expressed in ER positive cell lines (MCF7, MDA-MB-361, CAMA1) and lower in EGFR high cell lines (MDA-MB-468 and MDA-MB-231). CACNG4 knockdown inhibited cell migration and invasion in MCF7 and MDA-MB-231 cells. Conversely, cell adhesion and cell-cell aggregation was increased. RT-PCR revealed an inverse relation between CACNG4 expression and PKC-zeta specifically, which is involved in tight junction formation and shows low expression in breast, prostate and renal cancers. Thus, CACNG4 may play a role in de-adhesion and cell dissemination during metastasis. Blocking calcium channels with amlopidine had an anti-proliferative affect. Serum stimulation of EGFR high cell lines resulted in calcium influx, that was blocked in a dosage dependent manner with amlodipine, and synergistically blocked further with the EGFR specific tyrosine kinase inhibitor tryphostin AG1478. Knockdown of CACNG4 resulted in increased calcium influx suggesting a role in keeping the channel closed. Cells also showed resistance to amlodipine, requiring higher doses to block calcium influx. Conclusions: L-type channels are active in non-excitable breast cancer cells, and are affected by EGFR activity. CACNG4 maintains these channels in a closed state, modulating calcium influx, and inhibiting PKC-zeta expression which may result in metastatic function. The ability of calcium channel blockers to target channels in a CACNG4 dependent manner suggests novel treatment possibilities for invasive breast cancer. Citation Format: Nisha Kanwar, Ranju Nair, Dong-Yu Wang, Susan J. Done. The calcium channel subunit CACNG4 plays a role in breast cancer metastasis. [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 5116. doi:10.1158/1538-7445.AM2013-5116
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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 | 0.001 |
| 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".