期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1865, 期 9, 页码 1368-1382出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2018.06.010
关键词
Triple-negative breast cancer; Annexin A1; FPR1; Autocrine signaling; Cyclosporin H; Cyclosporin A
资金
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico Brasil (CNPq) [CNPq-465669/2014-0]
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [CBB-APQ-03613-17, CBB-APQ-0172612]
- Coordenadoria de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) [23038007281201161]
Breast Cancer (BC) is a highly heterogeneous disease whose most aggressive behavior is displayed by triple negative breast cancer (TNBC), which lacks an efficient targeted therapy. Despite its controversial role, one of the proteins that having been linked with BC is Annexin A1 (AnxA1), which is a Ca (+2) binding protein that acts modulating the immune system, cell membrane organization and vesicular trafficking. In this work we analyzed tissue microarrays of BC samples and observed a higher expression of AnxA1 in TNBCs and in lymph node metastasis. We also observed a positive correlation in primary tumors between expression levels of AnxA1 and its receptor, FPR1. Despite displaying a lesser strength, this correlation also exists in BC lymph node metastasis. In agreement, we have found that AnxA1 was highly expressed and secreted in the TNBC cell line MDA-MB-231 that also expressed high levels of FPR1. Furthermore, we demonstrated, by using the specific FPR1 inhibitor Cyclosporin H (CsH) and the immunosuppressive drug Cyclosporin A (CsA), the existence of an autocrine signaling of AnxA1 through the FPR1. Such signaling, elicited by AnxA1 upon its secretion, increased the aggressiveness and survival of MDA-MB-231 cells. In this manner, we demonstrated that CsA works very efficiently as an FPR1 inhibitor. Finally, by using CsA, we demonstrated that FPR1 inhibition decreased MDA-MB-231 tumor growth and metastasis formation in nude mice. These results indicate that FPR1 inhibition could be a potential intervention strategy to manage TNBCs displaying the characteristics of MDA-MB-231 cells. FPR1 inhibition can be efficiently achieved by CsA.
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