Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer.

Boopathi Subramaniyan,Sangita Sridharan,Elke Butt,Cory M Howard,Tupa Basuroy,Ivana De La Serna,Augustus M.C Tilley,Dayanidhi Raman

doi:10.3390/cancers12092372

Boopathi Subramaniyan, Sangita Sridharan + Show 6 more

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https://doi.org/10.3390/cancers12092372

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Abstract

The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.

Highlights

Breast cancer (BC) is a heterogeneous disease, and is the second leading cause of death in women among the cancer mortalities
Kaplan–Meier survival analysis to determine the probability of relapse-free survival when the expression of LASP1 and SNAI1 are high in human triple-negative breast cancer (TNBC) tumors
This study and others have found that the higher expression of LASP1 and SNAI1 was significantly correlated with lower relapse-free survival in TNBC patients with grade 3 tumors

Summary

Introduction

Breast cancer (BC) is a heterogeneous disease, and is the second leading cause of death in women among the cancer mortalities. Mortality in BC patients is mainly due to metastasis to the lungs, bone, and brain. Triple-negative breast cancer (TNBC) is a highly aggressive form of BC, with an increased risk of relapse, drug resistance, and metastases. The durable or pathological complete response (pCR) is low in TNBC patients [2,3,4,5]. There is mounting evidence to suggest that the CXCL12-CXCR4 axis plays an important role in triple-negative breast cancer (TNBC) progression and metastasis [6,7,8,9,10,11]. We reported that the N-terminal LIM domain of LIM and SH3 protein

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