94P - The tyrosine kinase AXL sustains EMT and tumour-associated inflammation in triple-negative breast cancers

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Carlotta Raschioni
Citation Annals of Oncology (2015) 26 (suppl_3): 31-33. 10.1093/annonc/mdv121
Authors C. Raschioni1, G. Bottai1, B. Szekely2, A. Losurdo3, L. Di Tommaso4, C. Tinterri5, L. Paladini1, J. Kulka2, M. Roncalli4, L. Santarpia1
  • 1Oncology Experimental Therapeutics Unit, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 22nd Department Of Pathology, Semmelweis University, Budapest/HU
  • 3Division Of Oncology And Hematology, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 4Department Of Pathology, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 5Breast Surgery Unit, Istituto Clinico Humanitas, 20089 - Rozzano/IT

Abstract

Body

Background: Triple-negative breast cancers (TNBC) lack effective therapeutic targets. This tumour subtype is characterized by epithelial-to-mesenchymal transition (EMT) features and dense immune cell infiltration, which are involved in tumour progression and response to chemotherapy. The aim of this study was to assess the potential correlation between tumour-associated macrophages (TAMs) and EMT-related tyrosine kinases and their biological relevance in TNBC.

Methods: Gene profiling analysis on publicly available TNBC datasets (N = 450) revealed a significant association between CD68 and AXL expression (P < 0.001). Immunohistochemical staining for CD68 (pan-macrophage marker), CD163 (M2 macrophage marker), and AXL was performed on archival tissues from 156 TNBCs, all treated with adjuvant taxane/anthracycline-containing chemotherapy. We validated our findings by in vitro experiments. Statistical analyses were performed using the Mann-Whitney, Spearman's correlation and Fisher's exact tests.

Results: TNBC patients who progressed on chemotherapy had a high CD163/CD68 ratio and AXL expression (P < 0.005). We found that CD163 was highly correlated with AXL expression in two independent TNBC cohorts (rs = 0.67, rs = 0.47; P < 0.001). Moreover, AXL was overexpressed in triple-negative compared to ER-positive breast cancer cell lines. AXL inhibition in TNBC cells reduced the expression of several EMT markers (e.g. Snail) and the activation of both AKT and ERK, decreasing the aggressiveness of breast cancer cells. AXL silencing also reduced the secretion of M2-polarizing cytokines, including IL-6 and IL-10. Furthermore, we found that TAMs activate NF-κB signalling, supporting EMT in cancer cells.

Conclusions: AXL and TAMs sustain EMT status in breast cancer, potentially leading to chemoresistance. Selective AXL inhibition may represent an effective anti-cancer treatment for TNBC patients.

Disclosure: All authors have declared no conflicts of interest.