High DNMT1 Expression in Stromal Fibroblasts Promotes Angiogenesis and Unfavorable Outcome in Locally Advanced Breast Cancer Patients.

Autor:	Al-Kharashi LA; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia., Tulbah A; Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Arafah M; Department of Pathology, King Saud University, Riyadh, Saudi Arabia., Eldali AM; Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Al-Tweigeri T; Department of Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Aboussekhra A; Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Jun 02; Vol. 12, pp. 877219. Date of Electronic Publication: 2022 Jun 02 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.877219
Abstrakt:	Background: Active breast cancer-associated fibroblasts (CAFs) play a leading role in breast carcinogenesis through promoting angiogenesis and resistance to therapy. Consequently, these active stromal cells have significant influence on patient outcome. Therefore, we explored here the role of the DNA methyltransferase 1 (DNMT1) protein in CAF-dependent promotion of angiogenesis as well as the prognostic power of DNMT1 level in both cancer cells and their adjacent CAFs in locally advanced breast cancer patients. Methods: We applied immunohistochemistry to evaluate the level of DNMT1 in breast cancer tissues and their adjacent normal counterparts. Quantitative RT-PCR and immunoblotting were performed to investigate the role of DNMT1 in regulating the expression of pro-angiogenic genes in active CAFs and also their response to the DNMT1 inhibitors decitabine (DAC) as well as eugenol. Results: We have shown that DNMT1 controls the pro-angiogenic potential of CAFs both in vitro and in vivo through positive regulation of the expression/secretion of 2 important pro-angiogenic factors VEGF-A and IL-8 as well as their upstream effectors mTOR and HIF-1α. To confirm this, we have shown that these DNMT1-related pro-angiogenic effects were suppressed by 2 DNMT1 inhibitors decitabine and eugenol. Interestingly, in a cohort of 100 tumors from locally advanced breast cancer patients (LABC), we have shown that high expression of DNMT1 in tumor cells and their adjacent stromal fibroblasts is correlated with poor survival of these patients. Conclusion: DNMT1 upregulation in breast stromal fibroblasts promotes angiogenesis via IL-8/VEGF-A upregulation, and correlates well with poor survival of LABC patients. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Al-Kharashi, Tulbah, Arafah, Eldali, Al-Tweigeri and Aboussekhra.)
Databáze:	MEDLINE
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