LOXL2 expression is associated with invasiveness and negatively influences survival in breast cancer patients

Abstract

Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in breast cancer. We analyzed the prognostic impact of LOXL2 for breast cancer patients and investigated the role of LOXL2 in breast cancer cell lines. Immunohistochemical study of LOXL2 expression was done in samples from 309 patients. Survival analysis was performed using log-rank test and Cox regression hazard model. After identification of LOXL2 expression in breast cancer cell lines, we performed matrigel invasion and wound-healing assays with LOXL2-silenced cell lines. In the human study, LOXL2 was expressed in 16.2 % of patients. Comparing the LOXL2-positive versus negative groups, there was a significantly higher proportion of estrogen receptor-negative patients (54.0 vs. 37.0 %, respectively; p = 0.029) and triple-negative patients (34.0 vs. 18.0 %; p = 0.022) in the positive group. In multivariate analysis for overall survival and metastasis-free survival, positive LOXL2 was demonstrated as a poor prognostic factor (HR 2.27 and 2.10, respectively). In vitro study indicated that LOXL2 silencing induces a mesenchymal-epithelial transition-like process in basal cell lines (MDA-MB-231 and BT549) associated with decreased invasive and migratory properties. These clinical and preclinical data confirm that higher LOXL2 expression is associated with invasiveness of basal-like breast cancer cells and lower survival of breast cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in breast cancer.

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

“…For instance, inhibition of LOX through pharmacological inhibition or injection with lysyl oxidase (LOX)-neutralizing antibodies reduced tumor metastasis from solid tumors (Levental et al 2009;Cox et al 2013;Pickup et al 2013). Similarly, studies using function-blocking antibodies to inhibit lysyl oxidase-like 2 (LOXL2) reduced collagen alignment and decreased tumor burden in a breast tumor xenograft (Grossman et al 2016); these antibodies have been associated with invasiveness and poor outcome in breast cancer (Ahn et al 2013). Higher LOXL2 levels are also associated with tumor invasion and poor outcome in pancreatic cancer patients and showed some efficacy in mouse models of PDAC (Park et al 2016).…”

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

“…LOX expression is often associated with specific tissues and biologic processes (9), and dysregulated expression was identified in many pathologic states (10)(11)(12). Elevated LOX expression is linked to the disrupted collagen morphology and increased tissue stiffness often found in tumors, leading to aberrant cellular behavior (10,13).…”

Recent Progress in Triple Negative Breast Cancer Research

“…Higher expression of LOXL2 was associated with poor outcome after a median follow-up time of 9.3 years. Moreover, preclinical and clinical data have clearly confirmed that the positive rate is higher in LOXL2 TNBC than non-TNBC tumors (Ahn et al, 2013).…”