Studying the role of RANKL in breast cancer and bone metastasis mouse models

e13045 Background: Compared to lumial breast cancer, the proporation of triple-negative breast cancer (TNBC) with bone metastases (BMs) is relatively low and few data focusing on the mechanism of the BMs in TNBC are available, Here, we screened that CTNND1 was associated with BMs of TNBC by integrating high-throughput sequencing, and further investigated the role of CTNND1 in BMs of TNBC in vitro. Methods: TNBC tissue samples with only BMs (n = 6) and without any metastasis (n = 10) were tested using high-throughput sequencing and 11 differentially expressed relative genes were identified. We then quantified these 11 genes in normal breast tissue samples (n = 26), TNBC tissue samples with only BMs (n = 10), TNBC tissue samples without any metastasis (n = 88) as well as luminal tissue samples with BMs（n = 10）through qPCR and immunohistochemical staining (IHC). The effects of knocking down CTNND1 on the interaction between TNBC cells and osteoblasts were examined by cell adhesion, transwell migration and matrigel invasion assays. To explorethe role of CTNND1 in mediating bone metastasis in TNBC, we used RNA-sequencing to find out the relative downstream gene CXCR4 and PI3K-AKT-mTOR pathway and verified it in vitro by Western Blotting. Results: Combining our high-throughput sequencing data, qPCR and IHC in clinical tissue samples, we verified that CTNND1 was decreased in TNBC patients with bone metastasis compared to normal tissue and luminal tissue with BMs. Knocking down of CTNND1 in TNBC cells including MDA-MB-231, MDA-MB-468 and BT549 weakened cells adhesion, but facilitated cells migration and invasion. Mechanically, knocking down of CTNND1 upregulated CXCR4 via activating PI3K-AKT-mTOR pathway in TNBC but not luminal and HER2- positive breast cancer cells lines. Conclusions: CTNND1 mediates bone metastasis in triple-negative breast cancer via regulating CXCR4.CTNND1 may serve as a potential predictor of bone metastasis for TNBC patients.

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Micro-imaging characterization of mouse models of metastasis

10.32469/10355/5820 ◽

2005 ◽

Author(s):

◽

Christopher Todd Winkelmann

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Mouse Models ◽

Bone Lesion ◽

Receptor Expression ◽

Bone Lesions ◽

Micro Ct ◽

Peptide Receptor ◽

Gastrin Releasing Peptide ◽

Models Of Disease

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Non-invasive imaging techniques have been recently developed to characterize animal models of disease. The overarching hypothesis of this work explores the use of three micro-imaging modalities, including Micro-CT, PET and SPECT, to characterize tumor anatomical progression, metabolism, bone lesion remodeling, and/or gastrin releasing peptide receptor expression in mouse models of metastatic melanoma and prostate and breast cancer bone metastasis. Micro-CT was shown to provide excellent anatomical information about tumor progression in several different tissues including lung, bone, and subcutaneous tissues. Micro-PET imaging demonstrated increased tumor metabolism in melanoma tumors, but was not able to discern bone remodeling in breast cancer bone lesions. Micro-SPECT imaging demonstrated gastrin-releasing peptide receptor expression in a prostate cancer bone metastasis model. The results from this work demonstrate the ability of micro-imaging technologies to non-invasively probe mouse models of disease to obtain information in vivo that is not possible with ex vivo experimental techniques.

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CXCR2: A Novel Mediator of Mammary Tumor Bone Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms20051237 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1237 ◽

Cited By ~ 4

Author(s):

Bhawna Sharma ◽

Kalyan Nannuru ◽

Sugandha Saxena ◽

Michelle Varney ◽

Rakesh Singh

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Tumor Cell ◽

Cancer Patients ◽

Mammary Tumor ◽

Critical Role ◽

Breast Cancer Patients ◽

Mammary Tumor Cell ◽

Primary Tumors

Most breast cancer patients die due to bone metastasis. Although metastasis accounts for 5% of the breast cancer cases, it is responsible for most of the deaths. Sometimes even before the detection of a primary tumor, most of the patients have bone and lymph node metastasis. Moreover, at the time of death, breast cancer patients have the bulk of the tumor burden in their bones. Therapy options are available for the treatment of primary tumors, but there are minimal options for treating breast cancer patients who have bone metastasis. C-X-C motif chemokine receptor type 2 (CXCR2) receptor-mediated signaling has been shown to play a critical role during bone-related inflammations and its ligands C-X-C motif chemokine ligand 6 (CXCL6) and 8 (CXCL8) aid in the resorption of bone during bone metastasis. In this study, we tested the hypothesis that CXCR2 contributes to mammary tumor-induced osteolysis and bone metastasis. In the present study, we examined the role of both tumor cell-derived and host-derived CXCR2 in influencing mammary tumor cell bone metastasis. For understanding the role of tumor cell-derived CXCR2, we utilized Cl66 CXCR2 knockdown (Cl66-shCXCR2) and Cl66-Control cells (Cl66-Control) and observed a significant decrease in tumor growth and tumor-induced osteolysis in Cl66-shCXCR2 cells in comparison with the Cl66-Control cells. Next, for understanding the role of host-derived CXCR2, we utilized mice with genomic knockdown of CXCR2 (Cxcr2−/−) and injected Cl66-Luciferase (Cl66-Luc) or 4T1-Luciferase (4T1-Luc) cells. We observed decreased bone destruction and metastasis in the bone of Cxcr2−/− mice. Our data suggest the importance of both tumor cell- and host-derived CXCR2 signaling in the bone metastasis of breast cancer cells.

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