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Osteotropism in breast cancer metastasis

ABSTRACT: Breast cancer metastases develop in the bone more frequently than any other site, and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression, and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver, and lung, closely mimicking the anatomical distribution of metastases in breast cancer patients. Using an in vivo selection process, we established NT2.5 sub-lines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sub-lines was performed.

ORGANISM(S): Mus musculus

PROVIDER: GSE47714 | GEO | 2013/06/07

SECONDARY ACCESSION(S): PRJNA207351

REPOSITORIES: GEO

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Osteotropism in breast cancer metastasis

Project description:Breast cancer metastases develop in the bone more frequently than any other site, and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression, and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver, and lung, closely mimicking the anatomical distribution of metastases in breast cancer patients. Using an in vivo selection process, we established NT2.5 sub-lines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sub-lines was performed. Individual samples of RNA from parental NT2.5 cells, early passage (BO3 and LI1) sub-lines, and final passage (BO6 and LI3) sub-lines were compared using GeneChip® Mouse Genome 430 2.0 Arrays

2013-06-07 | E-GEOD-47714 | biostudies-arrayexpress

Cancer stem cells from lobular infiltrating breast tumor metastasize to bone and acquire a gene signature associated to bone tropism

Project description:We investigated the role of breast cancer stem-like cells (CSCs-like), isolated from primary tumor, in promoting bone metastases in a human-in-mice model. Luciferase-transduced CD44+CD24- breast CSCs-like were injected through subcutaneous (SC) and intracardiac (IC) route in nonobese/severe combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The implanted bone was viable, active and human neo-vascularization was present. By in vivo luciferase imaging, we monitored tumor growth and detected bone-localized breast CSCs-like, both after SC and IC injection. Bone metastatic lesions were histologically evident, and tumor cells expressed epithelial markers and vimentin. Bone metastatic cells isolated from bone implants showed a CD44-CD24+ phenotype and re-created tumors and bone metastases after injection in secondary mice. A “bone tropism” expression signature was found to distinguish bone-colonizing cells from parental CSCs-like and to persist at subsequent passages also in the absence of surrounding bone tissue. The bone tropism signature displayed significant enrichment in genes discriminating bone metastases of breast cancer from metastases at other organs. Our results demonstrate the ability of breast CSCs-like to promote bone metastasis and provide a CSCs-like bone tropism signature, with potential prognostic value. C10 breast cancer stem-like cells (CSCs-like) were derived as mammospheres from a lobular-infiltrating breast carcinoma (ER+, HER2-). Samples are organized in the following groups: (i) Breast CSCs-like (C10, duplicate); (ii) Luciferase-transduced CSCs-like (C10L, simplicate); (iii) Bone-isolated C10L metastatic cells (C10-bone, duplicate) and subsequently (iv) grown in vitro as spheroids (C10-CSC, simplicate) or (v) re-grown in subcutaneous implants (C10-SC, duplicate).

2013-11-30 | E-GEOD-36102 | biostudies-arrayexpress

LC-MS/MS analysis of conditioned medium from primary breast cancer cells (PBCs#2/#3/#5) and bone-metastatic breast cancer cells (BMBCs#2/#3/#5)

Project description:Bone is the most common metastasis site in patients with breast cancer, and approximately up to 80% of patients with advanced breast cancer (BC) develop bone metastasis (BM), which leads to a worse prognosis with a median survival of 16 months and skeletal-related events (SREs), including severe bone pain, pathological fracture, hypercalcemia and lethal complications. Using quantitative proteomics mass-spectrometry (MS) analysis of the secretome from patient-derived primary BC cells (PBCs) and bone-metastatic BC cells (BMBCs), we identified an unreported breast cancer (BC) cells–secreted microprotein, osteolysin, encoded by tropomyosin 3 pseudogene 9 (TPM3P9) and clinically associated with BC bone-tropism.

2024-07-05 | PXD053732 |

Cancer stem cells from lobular infiltrating breast tumor metastasize to bone and acquire a gene signature associated to bone tropism

2013-11-30 | GSE36102 | GEO

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

Project description:Bone is the primary site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased quality of life in these patients. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture micro-dissected trephine biopsies of both breast cancer bone metastases and primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared to primary mammary tumors. Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary mammary tumors. In addition, ABCC5 was significantly up-regulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 significant reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers. Conclusions: Our data, for the first time, suggests that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for the efficient bone resorption mediated by osteoclasts. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis. primary breast tumors vs. bone trephine biopsies

2012-11-09 | E-GEOD-39494 | biostudies-arrayexpress

Increased Matrix Rigidities Modulate Interleukin Gene Signatures in ER+ Breast Cancer

Project description:Metastases of breast cancer is a prevalent problem with over 25% of patients suffering with metastatic disease. Of the patients that present with metastatic disease, the majority are estrogen receptor positive (ER+) and have skeletal metastases. These skeletal metastases can cause several issues including pathological fractures, chronic pain, and hypercalcemia. Currently, there are not any cures for metastatic breast cancer in bone and only therapies to mediate the osteolysis caused by breast cancer. The bone microenvironment presents various physical forces that can act on the tumor cell that has been studied in ER- cells, however, the physical forces on ER+ tumor cells have not been widely evaluated. In this study, we explored the transcriptional changes that occur at different matrix rigidities associated with the bone microenvironment (bone marrow: 0.5 kPa to 32 kPa; cortical and trabecular bone – 2 x 107 kPa). We observed that lower stiffnesses contributed to increased gene signatures associated with interleukin signaling. Additionally, we observed that downstream estrogen signaling outputs were modified. These interesting findings give us insights on what may be changing when ER+ tumor cells encounter rigidities associated with the bone microenvironment.

2024-09-09 | GSE274519 | GEO

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

2012-11-09 | GSE39494 | GEO

Mechanisms and pathways of bone metastasis: challenges and pitfalls of performing molecular research on patient samples

Project description:The molecular mechanisms underlying the development of bone metastases in breast cancer remain unclear. Disseminated tumour cells (DTCs) in the bone marrow of breast cancer patients are commonly identified, even in early stage disease, but their potential to initiate metastases is not known. The mechanism whereby DTCs become overt metastatic tumour cells (MTCs) is therefore, an area of considerable interest. This study explored the analysable yield of genetic material from human biopsy samples in order to describe differences in gene expression between DTCs and bone MTCs. Thirteen breast cancer patients with bone metastases underwent a CT-guided bone metastasis biopsy and a bone marrow biopsy. Tumour cells were enriched and gene expression profiling was conducted to identify differentially expressed genes. The analysable yield of sufficient RNA for microarray analysis was 60% from bone metastasis biopsies and 80% from bone marrow biopsies. A signature of 133 candidate genes differentially expressed between DTCs and MTCs was identified. Several genes relevant to breast cancer metastasis to bone (osteopontin, CTGF, parathyroid hormone receptor, EGFR) were significantly overexpressed in MTCs as compared to DTCs. Biopsies of bone metastases and bone marrow rarely yield enough tissue for robust molecular biology studies using clinical samples. The findings obtained however are interesting and seem to overlap with the bone metastasis gene expression signature described in murine xenograft models. Larger biopsy specimens or improved RNA extraction techniques may improve analysable yield and feasibility of these techniques. Gene expression profiling was utilized to compare DTCs obtained from bone marrow aspirates (A) to MTCs isolated from Computed Tomography (C) guided biopsies of bone metastases.

2012-07-05 | E-GEOD-14776 | biostudies-arrayexpress

Microarray analysis of human bone metastases samples

Project description:We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from breast cancer patients with only bone metastases and metastases in bone and visceral organs.

2011-12-29 | GSE34485 | GEO

Expression data from breast cancer bone metastasis [EO771]

Project description:The goal of this study was to evaluate genes that are differentially expressed in the bone stroma when breast cancer metastasis are present. We focused our attention on bone stroma cells to understand how the dissemination and growth of tumor cells can impact on the bone environment. Moreover, we aimed to identify potential targets to inhibit the cross talk between cancer cells and tumor microenvironment in bone metastasis. EO771 breast cancer cell line were engineered to express luciferase and GFP, and injected in C57BL/6 mice by the intracardiac route to obtain bone metastasis. Tumor growth was monitored in-vivo by bioluminescence for 2 weeks. Endothelial cells and osteoblasts were isolated from the long bones of tumor-bearing and tumor-free mice to identify genes differentially expressed.

2017-02-23 | GSE66205 | GEO

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