Lysyl Oxidase (LOX) Family Proteins: Key Players in Breast Cancer Occurrence and Progression

Abstract

The lysyl oxidase (LOX) family proteins are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like 1-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumours, whereby a corrupt tumour microenvironment (TME) takes shape. Additionally, dysregulation and aberrant expression of LOX family proteins have been implicated in the occurrence and progression of various types of human cancers, including lung cancer, hepatocellular carcinoma, gastric cancer, renal cell carcinoma, and colorectal cancer. Breast cancer is the most prevalent malignant tumour in women worldwide, and its incidence rate is increasing annually. In recent years, a growing body of evidence has revealed significant upregulation of LOX family proteins in breast cancer, which contributes to cancer cell proliferation, invasion, and metastasis. Furthermore, elevated expression of LOX family proteins is closely associated with poor prognosis in breast cancer patients. We herein review the structure, regulation, function, and mechanisms of LOX family proteins in the occurrence and progression of breast cancer. In addition, we highlight recent insights into their mechanisms and their potential involvement in the clinical value and novel biological roles of LOX family members in tumour progression and the TME of breast cancer. This review will provide a theoretical basis and reference for clinical diagnosis and treatment of breast cancer, as well as for the screening of effective LOX-specific inhibitors.

Keywords: breast cancer; extracellular matrix (ECM); family proteins; invasion and metastasis; lysyl oxidase (LOX); prognosis.

Figure 1

The structure of lysyl oxidase (LOX) family proteins. LOX family members encoded by the human LOX/LOXLs genes are located at various chromosome sites, including 5q23.1, 15q24.1, 8p21.3, 2p13.1, and 10q24.2. These members consist of a variable N-terminal domain and a highly conserved C-terminal domain. Si, signal peptide (Si); scavenger receptor cysteine-rich (SRCR); proline-rich region (PPR); copper binding domain (Cu²⁺); lysyl-tyrosyl-quinone (LTQ) co-factor; cytokine receptor-like domain (CRL).

Figure 2

Expression of LOX family mRNAs in breast cancer (with tumour and normal samples) from TCGA database. (A) Expression of LOX mRNA in breast cancers and normal breast samples. (B) Expression of LOXL1 mRNA in breast cancers and normal breast samples. (C) Expression of LOXL2 mRNA in breast cancers and normal breast samples. (D) Expression of LOXL3 mRNA in breast cancers and normal breast samples. (E) Expression of LOXL4 mRNA in breast cancers and normal breast samples. The Cancer Genome Atlas (TCGA); breast cancer (BRCA)

Figure 3

The OS and DFS curve of LOX family proteins in breast cancer. (A) The relationship of the LOX mRNA expression with the OS of breast cancer patients. (B) The relationship of the LOX mRNA expression with the DFS of breast cancer patients. (C) The relationship of the LOXL1 mRNA expression with the OS of breast cancer patients. (D) The relationship of the LOX L1 mRNA expression with the DFS of breast cancer patients. (E) The relationship of the LOXL2 mRNA expression with the OS of breast cancer patients. (F) The relationship of the LOXL2 mRNA expression with the DFS of breast cancer patients. (G) The relationship of the LOXL3 mRNA expression with the OS of breast cancer patients. (H) The relationship of the LOXL3 mRNA expression with the DFS of breast cancer patients. (I) The relationship of the LOXL4 mRNA expression with the OS of breast cancer patients. (J) The relationship of the LOXL4 mRNA expression with the DFS of breast cancer patients. Overall survival (OS); disease free survival (DFS).

Figure 4

Hypothetical model of LOX activity in promoting tumour progression in breast cancer. LOX is secreted as an inactive proLOX into the ECM where it is cleaved by BMP-1 to become the catalytically active LOX enzyme. Subsequently, active LOX can either translocate into the cell or remain in the ECM. Currently, it is not known where LOX target substrates localize. Subsequent catalytic interaction with substrate produces hydrogen peroxide and stimulates Src activation. Activated Src subsequently activates FAK (leading to changes in cell-matrix adhesion) and/or activates the p130Cas/Crk/DOCK180 signaling pathway (facilitating actin filament formation). Activation of Src may also lead to activation of the STAT3 and NFkB; however, this has not been validated in breast cancer cells. Together, stimulation of these pathways by LOX leads to cell motility and tumour progression in breast cancer. Extracellular matrix (ECM); bone morphogenic protein-1 (BMP-1); focal adhesion kinase (FAK); sarcoma gene (Src); signal transducer and activator of transcription 3 (STAT3); nuclear factor kappa B (NFkB).