Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

Yotsumoto, Fusanori; Tokunaga, Eriko; Oki, Eiji; Maehara, Yoshihiko; Yamada, Hiromi; Nakajima, Kyoko; Nam, Sung Ouk; Miyata, Koichiro; Koyanagi, Midori; Doi, Keiko; Shirasawa, Senji; Kuroki, Masahide; Miyamoto, Shingo

doi:10.1158/1541-7786.mcr-12-0428

Cited by 44 publications

(36 citation statements)

References 44 publications

(52 reference statements)

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“…These key cells contribute to the vicious cycle by expressing receptor activator of nuclear kappa B ligand (RANKL) - a signaling molecule that promotes the activity of bone-resorbing osteoclasts. Increased bone resorption results in the release of sequestered bone derived factors that in turn drive PCa growth thus completing the cycle (Yotsumoto 2013). The process by which prostate cancer to bone metastases successfully and establish in the bone microenvironment is less clear.…”

Section: Introductionmentioning

confidence: 99%

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases

et al. 2018

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Prostate cancer (PCa) impacts over 180,000 men every year in the USA alone, with 26,000 patients expected to succumb to the disease ( cancer.gov ). The primary cause of death is metastasis, with secondary lesions most commonly occurring in the skeleton. Prostate cancer to bone metastasis is an important, yet poorly understood, process that is difficult to explore with experimental techniques alone. To this end we have utilized a hybrid (discrete-continuum) cellular automaton model of normal bone matrix homeostasis that allowed us to investigate how metastatic PCa can disrupt the bone microenvironment. Our previously published results showed that PCa cells can recruit mesenchymal stem cells (MSCs) that give rise to bone-building osteoblasts. MSCs are also thought to be complicit in the establishment of successful bone metastases (Lu, in Mol Cancer Res 4(4):221-233, 2006). Here we have explored the aspects of early metastatic colonization and shown that the size of PCa clusters needs to be within a specific range to become successfully established: sufficiently large to maximize success, but not too large to risk failure through competition among cancer and stromal cells for scarce resources. Furthermore, we show that MSC recruitment can promote the establishment of a metastasis and compensate for relatively low numbers of PCa cells seeding the bone microenvironment. Combined, our results highlight the utility of biologically driven computational models that capture the complex and dynamic dialogue between cells during the initiation of active metastases.

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Section: Introductionmentioning

confidence: 99%

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases

et al. 2018

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“…This suggested post-transcriptional regulation of HOXA9 expression in lrECM 3D culture. A survey of a recent gene expression profiling (GSE36953) confirmed widespread differential expression of the HOX genes between 2D and lrECM 3D cultures of MDA-MB-231 cells (Supplementary Materials Table S2) [26]. In 2D culture, MDA-MB-231 cells exhibited mesenchymal cell like morphoglogy that featured absence of cell-cell adhesion and robust expression of vimentin, a mesenchymal cell-specific intermediate filament (1E).…”

Section: Resultsmentioning

confidence: 95%

Induction of HOXA9 expression in three-dimensional organotypic culture of the Claudin-low breast cancer cells

Zhuang

et al. 2016

Oncotarget

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The gene expression signatures of the molecular intrinsic subtypes of breast cancer are regulated by epigenetic mechanisms such as methylation of CpG islands in gene promoters. Epigenetic codes can be regulated by the tumor microenvironment. The Claudin-low subtype is associated with triple-negative invasive ductal carcinomas in patients. Herein we explored epigenetic regulation of gene expression in the Claudin-low breast cancer cells by extracellular matrix (ECM), a key component of the tumor microenvironment. We modeled attachment to ECM using laminin rich ECM three-dimensional organotypic culture (lrECM 3D). In 2D and lrECM 3D cultures we examined expression of the homeobox (HOX) genes that epigenetically regulated in development and cancer. We demonstrated induction of the selected HOX genes in lrECM 3D culture of the Claudin-low breast cancer cells MDA-MB-231 and Hs578T. In particular activation of HOXA9 expression in lrECM 3D culture required binding of bromodomain containing 4 to the HOXA9 promoter and involved CpG hypomethylation. Our findings warrant further investigation of the ECM-regulated epigenetic coding of gene expression in the Claudin-low breast cancer.

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“…1B). Induction of HOTAIR was also observed in gene expression profiling (GEO GSE36953) of lrECM 3D culture of MDA‐MB‐231 (Yotsumoto et al ., 2013). Induction of HOTAIR correlated with invasive growth of MDA‐MB‐231 cells and Hs578T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

Zhuang

et al. 2017

Molecular Oncology

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Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin‐low MDA‐MB‐231 and Hs578T cells in two‐dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin‐rich extracellular matrix‐based three‐dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR‐specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR‐N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR‐N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR‐N promoter in Claudin‐low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin‐low breast cancer cells in lrECM 3D culture.

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Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer

Cited by 44 publications

References 44 publications

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases

Size Matters: Metastatic Cluster Size and Stromal Recruitment in the Establishment of Successful Prostate Cancer to Bone Metastases

Induction of HOXA9 expression in three-dimensional organotypic culture of the Claudin-low breast cancer cells

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

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