Abstract 4587: Dynactin dysregulation-induced increase in EGFR on basal-like breast cancer cells
| العنوان: | Abstract 4587: Dynactin dysregulation-induced increase in EGFR on basal-like breast cancer cells |
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| المؤلفون: | Smita Misra, Gautam Chaudhuri |
| المصدر: | Cancer Research. 76:4587-4587 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Cancer Research, biology, Cell, Cancer, medicine.disease, DCTN1, Transcriptome, medicine.anatomical_structure, Oncology, microRNA, Immunology, medicine, Cancer research, biology.protein, Dynactin, Epidermal growth factor receptor, ACTR1A |
| الوصف: | Aggressive triple-negative basal-like breast cancer (BLBC) cells are often characterized with overabundance of the epidermal growth factor receptor (EGFR). Major objective of our research is to explore the possibility that dysregulation of the function of the dynactin complex as a mechanism of over-abundance of EGFR on BLBC cell surface. Our notion is that molecular defects in the dynactin-mediated retrograde EGFR recycling pathway in the BLBC cells causes the accumulation of this receptor on their cell surface making them hyper-responsive to EGF signaling. Our comparative transcriptome analysis between BLBC cells with higher levels of EGFR and the non-BLBC cells with lower levels of EGFR revealed that the expression of dynactin complex subunits 1, 2, 3, 4 and 6 (DCTN1, 2, 3, 4, 6), are significantly reduced in the EGFR-high aggressive BLBC cells. In addition, EGFR-high BLBC cells also have lower levels of two other dynactin-associated proteins, CLIP1 and LRRK1. Interestingly, elevation of surface EGFR levels in BLBC cells are associated with higher levels of the long non-coding RNA PVT1. Six miRNAs are generated from the precursor of PVT1 RNA during cis-splicing. They are miR-1204, miR-1205, miR-1206, miR-1207-3p, miR-1207-5p and miR-1208. We found that relative levels of these miRNAs are significantly higher in EGFR-high BLBC cells and tissues in comparison to the non-aggressive EGFR-low BLBC cells. Bioinformatics analysis followed by experimental validation revealed that miR-1207-5p inhibits DCTN1, DCTN3 and ACTR1A; DCTN2 is inhibited by miR-1205 and miR-1208. MiR-1208 also inhibits DCTN6 and CLIP1 whereas LRRK1 and CAPZA1 are inhibited by miR-1207-3p and miR-1206, respectively. Moreover beta-spectrin (SPTB), a protein associated with dynactin complex, is also inhibited by miR-1205 and miR-1207-3p. Treatment of the cells with the antagomirs of the miRNAs increased the levels of their respective target proteins with concomitant decrease in the surface level of EGFR. Our data suggest that BLBC cells maintain a robust level of EGFR on the cell surface by repressing the retrograde transport of EGFR through the repression of the proteins in the dynactin complex and thus sustain their higher growth rates. This research is supported in part by DOD-CDMRP IDEA Expansion Grant# BC103645 and NIH/NCI grant 1R21CA181920-01 to GC. Citation Format: Gautam Chaudhuri, Smita Misra. Dynactin dysregulation-induced increase in EGFR on basal-like breast cancer cells. [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 4587. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::cfc0e6097a4d6fe3bc4d587b33857b5b https://doi.org/10.1158/1538-7445.am2016-4587 |
| رقم الأكسشن: | edsair.doi...........cfc0e6097a4d6fe3bc4d587b33857b5b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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