Abstract
Lysyl oxidase (LOX) family genes catalyze collagen cross-link formation. To determine the effects of lysyl oxidase-like 4 (LOXL4) expression on breast tumor formation and metastasis, we evaluated primary tumor growth and lung metastasis in mice injected with LOXL4-knockdown MDA-MB-231 triple-negative human breast cancer cells. In addition, we analyzed overall survival in breast cancer patients based on LOXL4 expression using a public online database. In the mouse xenograft model, LOXL4 knockdown increased primary tumor growth and lung colonization as well as collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging revealed that LOXL4 knockdown resulted in the thickening of collagen bundles within tumors. In addition, weak LOXL4 expression was associated with poor overall survival in breast cancer patients from the BreastMark dataset, and this association was strongest in triple-negative breast cancer patients. These results demonstrate that weak LOXL4 expression leads to remodeling of the extracellular matrix through induction of collagen synthesis, deposition, and structural changes. These alterations in turn promote tumor growth and metastasis and are associated with poor clinical outcomes in triple-negative breast cancer.
Highlights
Elevated collagen deposition and alterations in the structure of the extracellular matrix (ECM) are common in various forms of cancer [1, 2]
We demonstrated that knockdown of lysyl oxidase-like 4 (LOXL4) expression promoted primary tumor growth and lung metastasis in MDA-MB-231 cell xenograft models of breast cancer
We found that low LOXL4 expression was associated with poorer overall survival in breast cancer patients
Summary
Elevated collagen deposition and alterations in the structure of the extracellular matrix (ECM) are common in various forms of cancer [1, 2]. LOXL4, LOX, and LOXL2, which are expressed in a hypoxia-inducible factor 1-dependent manner, recruit bone marrow-derived www.impactjournals.com/oncotarget cells and facilitate colonization of the lungs [19] These conflicting results might be explained by differences in the cellular context among cancers that might influence whether LOXL4 acts as a tumor suppressor or a metastasis promoter. A recent report revealed that, among the LOX family members, LOXL4 mRNA levels alone were higher in cancer tissues from TNBC patients than in those from estrogen receptorpositive breast cancer patients [22] These reports suggest that LOXL4 expression might affect clinical outcomes in TNBC patients, to the best of our knowledge, no studies have directly examined this relationship. We evaluated the clinical significance of LOXL4 in human breast cancer patients using a public database with overall survival (OS) information
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