Potential options for managing LOX+ ER− breast cancer patients

Han, Yong; Lian, Shenyi; Cui, Xingran; Meng, Kexin; Győrffy, Balázs; Jin, Tao; Huang, Dongsheng

doi:10.18632/oncotarget.9073

Cited by 12 publications

(12 citation statements)

References 31 publications

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“…Future studies will evaluate the importance of ATP7A in other cancer models, including models of spontaneous cancer. Previous studies have demonstrated that elevated LOX expression is correlated with poor survival of ER-negative breast cancer patients (38). Consistent with a requirement for ATP7A in LOX activity, we found that high ATP7A expression correlates with decreased survival in patients with ER-negative breast cancer (Fig.…”

Section: Discussionsupporting

confidence: 89%

“…Cancer Patients. Previous studies have shown that high LOX expression is correlated with reduced survival in patients with estrogen receptor (ER)-negative breast cancer (38). We used publicly available databases to investigate the degree to which patient mortality is correlated with ATP7A mRNA expression in breast tumors.…”

Section: Atp7a Expression Is Correlated With Reduced Survival In Breastmentioning

confidence: 99%

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ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

Shanbhag

Jasmer

Zhu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

152

109

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Lysyl oxidase (LOX) and LOX-like (LOXL) proteins are copperdependent metalloenzymes with well-documented roles in tumor metastasis and fibrotic diseases. The mechanism by which copper is delivered to these enzymes is poorly understood. In this study, we demonstrate that the copper transporter ATP7A is necessary for the activity of LOX and LOXL enzymes. Silencing of ATP7A inhibited LOX activity in the 4T1 mammary carcinoma cell line, resulting in a loss of LOX-dependent mechanisms of metastasis, including the phosphorylation of focal adhesion kinase and myeloid cell recruitment to the lungs, in an orthotopic mouse model of breast cancer. ATP7A silencing was also found to attenuate LOX activity and metastasis of Lewis lung carcinoma cells in mice. Metaanalysis of breast cancer patients found that high ATP7A expression was significantly correlated with reduced survival. Taken together, these results identify ATP7A as a therapeutic target for blocking LOX-and LOXL-dependent malignancies.breast cancer | lung cancer | copper | lysyl oxidase | metastasis

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Section: Discussionsupporting

confidence: 89%

Section: Atp7a Expression Is Correlated With Reduced Survival In Breastmentioning

confidence: 99%

ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

Shanbhag

Jasmer

Zhu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

152

109

View full text Add to dashboard Cite

show abstract

“…It has been previously reported that LOX enhances the metastatic trait of breast tumors in animals by stimulating TWIST1 expression in tumor cells (8). In addition, LOX overexpression in breast cancer has been associated with EMT of tumor cells (28). Here, LOX overexpression in Hct116 cells did not modify the morphologic appearance of these cells and it did not modify the expression of transcription factors TWIST1 and SNAI1, indicating that LOX in colorectal cancer cells did not contribute to tumor cell dissemination in bone by promoting an EMT.…”

Section: Discussionmentioning

confidence: 97%

Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone

et al. 2017

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Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1 In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases. In vivo experimental studies show that LOX overexpression in colorectal cancer cells or systemic delivery of the conditioned medium from LOX-overexpressing colorectal cancer cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1 Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of colorectal cancer cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in colorectal cancer cells also induced a robust production of IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between bone resorption and bone formation. Collectively, our findings show that LOX supports colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL6 production by colorectal cancer cells impairs bone homeostasis. Cancer Res; 77(2); 268-78. ©2016 AACR.

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“…It has only been reported that LOX is regulated by HIF-1α under hypoxia and is induced by TGF-β in cancer cells, the mechanisms are still largely uncovered. Studies on LOX previously focused on breast cancer ( Wuest et al, 2015 ; Han et al, 2016 ). However, we found that LOX expression is more related to the poor prognosis of lung adenocarcinoma, as is shown in Figure 1 .…”

Section: Discussionmentioning

confidence: 99%

Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway

Hou

Quan

et al. 2018

Front. Pharmacol.

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Tumor metastasis is the most lethal and debilitating process that threatens cancer patients. Among the regulators involved in tumor metastasis, lysyl oxidase (LOX) is an important contributor for tumor invasion, migration and the formation of the pre-metastatic niche. Although the relationship between LOX and poor prognosis of lung patients has been preliminary reported, the mechanism remains poorly understood. Here, we found that LOX overexpression is closely related to the survival of lung adenocarcinoma patients but not squamous cell carcinoma patients. Moreover, we confirmed that LOX expression is regulated by the activation of epidermal growth factor receptor (EGFR) via the PI3K/AKT, MEK/ERK, and SAPK/JNK signaling pathways in non-small cell lung cancer (NSCLC). Meanwhile, the study also suggested that the traditional anti-fibrosis drug silibinin inhibited NSCLC cell migration in an EGFR/LOX dependent manner. In addition, an orthotopic implantation metastasis model also confirmed that the EGFR inhibitor WZ4002 and silibinin decreased tumor metastasis through the EGFR/LOX pathway. Altogether, this study revealed that LOX expression is regulated by the EGFR pathway and this may account for the anti-cancer metastasis effects of silibinin, indicating LOX as a potentially therapeutic target for NSCLC treatment.

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Potential options for managing LOX+ ER− breast cancer patients

Cited by 12 publications

References 31 publications

ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone

Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway

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