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Biochim Biophys Acta Mol Cell Res. 2018 Sep;1865(9):1368-1382. doi: 10.1016/j.bbamcr.2018.06.010. Epub 2018 Jun 20.

Inhibition of the AnxA1/FPR1 autocrine axis reduces MDA-MB-231 breast cancer cell growth and aggressiveness in vitro and in vivo.

Author information

1
Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, MG, Brazil. Electronic address: laravecchi7@yahoo.it.
2
Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, MG, Brazil.
3
International Research Center, AC Camargo Cancer Center, São Paulo, SP, Brazil.
4
Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
5
Department of Investigative Pathology, AC Camargo Cancer Center, São Paulo, Brazil.
6
Laboratory of Biochemistry and Animal Toxins, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, MG, Brazil.
7
Immunopathology Laboratory, Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, UNESP, São Jose do Rio Preto, São Paulo, Brazil.
8
Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, Uberlândia, MG, Brazil. Electronic address: lrgoulart@ufu.br.

Abstract

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.

KEYWORDS:

Annexin A1; Autocrine signaling; Cyclosporin A; Cyclosporin H; FPR1; Triple-negative breast cancer

PMID:
29932988
DOI:
10.1016/j.bbamcr.2018.06.010
[Indexed for MEDLINE]

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