Abstract
Simple SummaryDistant metastasis, especially bone metastasis, is the major cause of death in breast cancer patients. However, breast cancer patients with bone metastasis are frequently complicated by delayed intervention as clinically bone metastasis cannot be detected early enough. Here, we report that CTNND1 is downregulated in both primary tumors and metastatic bone lesions of patients with triple-negative breast cancer (TNBC). Decreased CTNND1 is a crucial intrinsic contributor to homing to the bones and the survival of the breast cancer cells in the bone microenvironment. Thus, CTNND1 may be a novel biomarker for early predicting bone metastasis of triple-negative breast cancer.Bone metastasis from triple-negative breast cancer (TNBC) frequently results in poorer prognosis than other types of breast cancer due to the delay in diagnosis and intervention, lack of effective treatments and more skeletal-related complications. In the present study, we identified CTNND1 as a most reduced molecule in metastatic bone lesion from TNBC by way of high throughput sequencing of TNBC samples. In vivo experiments revealed that knockdown of CTNND1 enhanced tumor cells metastasis to bones and also increased neutrophils infiltration in bones. In vitro, we demonstrated that knockdown of CTNND1 accelerated epithelial–mesenchymal transformation (EMT) of tumor cells and their recruitment to bones. The involvement by CTNND1 in EMT and bone homing was achieved by upregulating CXCR4 via activating the PI3K/AKT/HIF-1αpathway. Moreover, TNBC cells with reduced expression of CTNND1 elicited cytotoxic T-cells responses through accelerating neutrophils infiltration by secreting more GM-CSF and IL-8. Clinically, patients with triple-negative breast cancer and lower level of CTNND1 had shorter overall survival (OS) and distant metastasis-free survival (DMFS). It was concluded that downregulation of CTNND1 played a critical role in facilitating bone metastasis of TNBC and that CTNND1 might be a potential biomarker for predicting the risk of bone metastases in TNBC.
Highlights
Female breast cancer (BC) is a heterogenous and complex disease and has become the leading cancer type in global cancer incidence [1]
We further demonstrated that knockdown of Catenin Delta 1 (CTNND1) enhanced intrinsic metastatic functions including migration and invasion, and facilitated tumor recruitment to bones, an event through the CXCR4/CXCL12 axis by activating PI3K/AKT/HIF-1α pathway
To investigate the molecular profile of metastatic bone lesions derived from triplenegative breast cancer (TNBC), high-throughput sequencing was performed in cohort 1, which included metastatic bone lesions from three patients who had only bone metastases and three early TNBC patients without any signs of distant metastasis
Summary
Female breast cancer (BC) is a heterogenous and complex disease and has become the leading cancer type in global cancer incidence [1]. In BC patients, distant metastases, rather than the primary tumors, are the main cause of death. Of the location of distant metastases, bone is the most common site [2]. Current treatments for bone metastasis of breast cancer involve multiple and often combined approaches ranging from conventional surgical, drug and radiation therapies to newly developed biological drugs, targeted treatment and gene therapy [3,4,5]. Amongst the subtypes of breast cancer, triplenegative breast cancer (TNBC) is a recognized subtype that is difficult to treat, as those treatments targeting these receptors are not effective for this tumor type [5,6]. Compared with the luminal subtype, TNBC patients with bone metastasis have poorer outcomes as the risk of bone metastasis cannot be early and accurately predicted [3,7,8,9]
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