Abstract 5055: SPEN stimulates primary cilia formation, cell migration and is associated with metastasis in breast cancer
Bibliographic record
Abstract
Abstract The primary cilium (PC) is a microtubule-based and non-motile organelle that functions as animal cells’ antennae, regulating a number of signalling pathways, including the mTOR, PDGFR and Wnt pathways, in addition to being essential for activation of the canonical Hedgehog (Hh) pathway. In breast cancer, the PC is a structure that is frequently lost due to transcription- and mutation-driven alterations in cilium-related genes. In a study aiming to delineate the hormone-independent transcriptional program regulated by SPEN, a gene that we have identified as a tumour suppressor gene in estrogen receptor (ER)-positive breast cancers, we found that SPEN was co-expressed (R>0.95) with a number of genes involved in ciliary biology (P = 1.64E-19), including the ciliogenic transcription factors RFX2, RFX3 and FOXJ1. Interestingly, the overexpression of SPEN resulted in the restoration of the PC in T47D cells, which have previously been shown to lack this structure. Consistent with the re-establishment of a PC in T47D cells, SPEN-overexpressing T47D cells had decreased mTOR signalling, hyperactivation of PC-dependent pathways, including the Hh and PDGFR pathways, and increased migration. Silencing SPEN expression in the non-tumorigenic MCF10A cells, which express high endogenous levels of SPEN and show a high prevalence of PC (36%), considerably decreased PC levels in MCF10A cells and was accompanied with increased mTORC1 activity as well as attenuated cell migration. We also found that SPEN silencing in MCF10A cells decreased the expression of the ciliogenic transcription factor RFX3 and that SPEN interacts with DNA upstream of RFX3 gene transcription start site in chromatin immunoprecipitation experiments. Collectively, these observations indicate that SPEN may mediate its effects, at least in part, through the transcriptional regulation of RFX3. Accordingly, RFX3 expression levels were strongly positively correlated (R = 0.55, P<0.0001) with SPEN levels in a cohort of 82 clinical samples from triple negative breast cancer patients. Notably, high SPEN RNA levels were also predictive of early metastasis in two independent cohorts of 77 (HR = 2.25, P = 0.03) and 170 (HR = 2.23, P = 0.004) ER-negative breast cancer patients. Together, our findings highlight a role for SPEN in the regulation of PC formation and support important functions in the inhibition of mTORC1 and activation of Hh and PDGFR pathways as well as cell migration, a process that may contribute to early metastasis in ER-negative breast cancers. Citation Format: Stéphanie Légaré, Catherine Chabot, Mark Basik. SPEN stimulates primary cilia formation, cell migration and is associated with metastasis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5055.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".