Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

Minami, Kazumasa; Liu, Shengzhi; Liu, Yang; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Li, Bai Yan; Matsuura, Nariaki; Koike, Masahiko; Yin, Yue-Ping; Gan, Liangying; Xu, Anlong; Li, Jiliang; Nakshatri, Harikrishna; Yokota, Hiroki

doi:10.1038/srep45686

Cited by 37 publications

(47 citation statements)

References 42 publications

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“…Breast cancer BMICs have been found to exhibit GABAergic properties, mimicking neuronal phenotypes that appear to aid their colonization of the brain (39). Dopamine receptors (DR) and dopamine have been revealed to exhibit various pleiotropic properties through dependent and independent pathways, and their modulation has enhanced the efficiency of anticancer drugs in preclinical cancer models (40,41). In particular, DRD2 agonists have recently been shown to suppress proliferation, angiogenesis, and invasion in several cancers and tumors (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis

et al. 2018

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Brain metastases (BM) result from the spread of primary tumors to the brain and are a leading cause of cancer mortality in adults. Secondary tissue colonization remains the main bottleneck in metastatic development, yet this "premetastatic" stage of the metastatic cascade, when primary tumor cells cross the blood-brain barrier and seed the brain before initiating a secondary tumor, remains poorly characterized. Current studies rely on specimens from fully developed macrometastases to identify therapeutic options in cancer treatment, overlooking the potentially more treatable "premetastatic" phase when colonizing cancer cells could be targeted before they initiate the secondary brain tumor. Here we use our established brain metastasis initiating cell (BMIC) models and gene expression analyses to characterize premetastasis in human lung-to-BM. Premetastatic BMIC engaged invasive and epithelial developmental mechanisms while simultaneously impeding proliferation and apoptosis. We identified the dopamine agonist apomorphine to be a potential premetastasis-targeting drug. treatment with apomorphine prevented BM formation, potentially by targeting premetastasis-associated genes , and Low expression of these genes was associated with poor survival of patients with lung adenocarcinoma. These results illuminate the cellular and molecular dynamics of premetastasis, which is subclinical and currently impossible to identify or interrogate in human patients with BM. These data present several novel therapeutic targets and associated pathways to prevent BM initiation. These findings unveil molecular features of the premetastatic stage of lung-to-brain metastases and offer a potential therapeutic strategy to prevent brain metastases. .

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis

et al. 2018

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“…Mice injected with mammary tumors in either location will be referred to as mice with breast cancer, mice with mammary pad tumors as localized and mice with tumors injected in the iliac artery as metastasized breast cancer. Injection into the iliac artery is an accepted model of metastasized cancer 29 . Bone is a common region where breast cancer metastasizes to because of the high affinity for bone that breast cancer cells exhibit 30,31 .…”

Section: Methodsmentioning

confidence: 99%

Detection of Volatile Organic Compounds (VOCs) in Urine via Gas Chromatography-Mass Spectrometry QTOF to Differentiate Between Localized and Metastatic Models of Breast Cancer

Woollam

Teli

Angarita-Rivera

et al. 2019

Sci Rep

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Breast cancer is the most common cancer detected in women and current screening methods for the disease are not sensitive. Volatile organic compounds (VOCs) include endogenous metabolites that provide information about health and disease which might be useful to develop a better screening method for breast cancer. The goal of this study was to classify mice with and without tumors and compare tumors localized to the mammary pad and tumor cells injected into the iliac artery by differences in VOCs in urine. After 4T1.2 tumor cells were injected into BALB/c mice either in the mammary pad or into the iliac artery, urine was collected, VOCs from urine headspace were concentrated by solid phase microextraction and results were analyzed by gas chromatography-mass spectrometry quadrupole time-of-flight. Multivariate and univariate statistical analyses were employed to find potential biomarkers for breast cancer and metastatic breast cancer in mice models. A set of six VOCs classified mice with and without tumors with an area under the receiver operator characteristic (ROC AUC) of 0.98 (95% confidence interval [0.85, 1.00]) via five-fold cross validation. Classification of mice with tumors in the mammary pad and iliac artery was executed utilizing a different set of six VOCs, with a ROC AUC of 0.96 (95% confidence interval [0.75, 1.00]).

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“…We selected a Chk1 inhibitor (PD407824) as well as a dopamine receptor D1 agonist (A77636), which reduced the proliferation of two cancer cell lines without significant reduction of proliferation of two non-tumor cell lines. The efficacy of A77636 in suppressing tumor growth and bone loss was reported previously [ 10 ].…”

Section: Introductionmentioning

confidence: 63%

Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model

Liu

Minami

et al. 2018

Oncotarget

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DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration.

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Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

Cited by 37 publications

References 42 publications

Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis

Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis

Detection of Volatile Organic Compounds (VOCs) in Urine via Gas Chromatography-Mass Spectrometry QTOF to Differentiate Between Localized and Metastatic Models of Breast Cancer

Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model

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