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

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 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.

Targeting ANXA1 abrogates Treg-mediated immune suppression in triple-negative breast cancer

“…On cell levels, ANXA1 autocrine axis could enhance MDA-MB-231 breast cancer cell growth and aggressiveness. 42 Our results suggest that ANXA1 is significant for Treg cells mediated anti-breast cancer immunity. First, increased plasma levels of ANXA1 in patients with breast cancer may provide clues to our diagnosis.…”

Identification of human peripheral blood monocyte gene markers for early screening of solid tumors

“…the preinvasive properties of malignant cancers through autocrine signaling induced by the Nterminal peptide [21].…”

Application of small molecule FPR1 antagonists in the treatment of cancers

“…We chose to study the efficacy of FPR1 antagonist ICT12035 in vitro and in vivo in the glioblastoma cell line, U87-MG. As we discussed earlier, the relevance of FPR1 as a target is shown in a number of cancers 13,[16][17][18][19][20][21][22][23][24][25][26]28,29 . However, the expression and the relevance of FPR1 in glioblastoma is established in multiple sources 31,32 .…”

“…Interestingly, the inflammatory response within tumours appears to both help and hinder tumour expansion 45 . In addition, ANXA1 appears to have a distinct tumour promoting effect by binding and activating FPR1, the expression of which is shown to be elevated in many tumours 13,[16][17][18][19][20][21][22] . The activation of FPR1 by ANXA1 promotes angiogenesis, proliferation, and invasion in a number of cancers 13,46 .…”

“…Ye has shown that FPR1 -/mice have increased survival compared with FPR +/+ littermates in a colorectal cancer model 20 . Finally, Vecchi and Goulart have shown that immunosuppressant cyclosporine A, which is also a weak antagonist of FPR1 (IC 50 = 2-4 μM in calcium mobilisation assay 27 ), retards tumour growth and invasiveness in a breast cancer in vivo model 21 . Whilst these studies suggest a direct role for FPR1 in tumour growth, evidence in ovarian 28 , glioma 17 and bladder cancers 22 as well as acute lymphoblastic leukaemia 29 , has suggested that FPR1 is also involved in resistance and recurrence.…”