Dataset Information

Bone-Induced Expression of Integrin ?3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

ABSTRACT: Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin ?3 (?3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, ?3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, ?3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGF? signaling through SMAD2/SMAD3 was necessary for breast cancer induction of ?3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin ?v?3 (?v?3-MPs of ?12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with ?v?3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin ?v?3 at that metastatic site. Cancer Res; 77(22); 6299-312. ©2017 AACR.

SUBMITTER: Ross MH

PROVIDER: S-EPMC5841166 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

Ross Michael H MH Esser Alison K AK Fox Gregory C GC Schmieder Anne H AH Yang Xiaoxia X Hu Grace G Pan Dipanjan D Su Xinming X Xu Yalin Y Novack Deborah V DV Walsh Thomas T Colditz Graham A GA Lukaszewicz Gabriel H GH Cordell Elizabeth E Novack Joshua J Fitzpatrick James A J JAJ Waning David L DL Mohammad Khalid S KS Guise Theresa A TA Lanza Gregory M GM Weilbaecher Katherine N KN

Cancer research 20170830 22

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on ...[more]

PMID: 28855208

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Project description:Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone.The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood samples are collected and detailed epidemiologic data is collected by in-person interview and self-administered questionnaires. Additional self-administered questionnaires and blood samples are completed at specified follow-up intervals (24, 48 and 72 months). Vital status is obtained prior to each follow-up through record linkages with the Alberta Cancer Registry. Recurrences are identified through medical chart abstractions. Each of the four projects applies specific methods and analyses to assess the impact of serum vitamin D and cytokine concentrations, tumour transcript and protein expression, serum metabolomic profiles and in vitro cell signalling on breast cancer bone metastases.The B2B Research Program will address key issues in breast cancer bone metastases including the association between lifestyle factors (particularly a comprehensive assessment of vitamin D status) inflammation and bone metastases, the significance or primary tumour gene expression in tissue tropism, the potential of metabolomic profiles for risk assessment and early detection and the signalling pathways controlling the metastatic tumour microenvironment. There is substantial synergy between the four projects and it is hoped that this integrated program of research will advance our understanding of key aspects of bone metastases from breast cancer to improve the prevention, prediction, detection, and treatment of these lesions.

Dataset Information

Bone-Induced Expression of Integrin ?3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

Publications

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

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