DLC1 Suppresses Breast Cancer Bone Metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46214 | GEO | 2013/12/19
SECONDARY ACCESSION(S): PRJNA198082
REPOSITORIES: GEO
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Project description:The skeleton is the most common metastasis site of breast cancer cells and the molecular underpinning of this process is incompletely understood. The tumor suppressor gene deleted in liver cancer-1 (DLC1) encodes a multi-domain protein including a RhoGTPase activating protein (RhoGAP) domain and has been reported to suppress the lung colonization of breast cancer cells. However, the role of DLC1 in breast cancer bone metastasis and the importance of RhoGAP-dependent and -independent pathways in this process remain unclear. Here, we showed that DLC1 silencing is linked to enhanced bone-tropism of breast cancer cell lines and poor prognosis of clinical samples. In the study presented here, DLC1 was overexpressed in the SCP2 breast cancer cells, and the control SCP2 and overexpression cells were treated with TGFbeta. Microarray profiling of mRNA levels was performed in the control and overexpression cells with or without TGFbeta treatment.
2013-12-19 | E-GEOD-46214 | biostudies-arrayexpress
Project description:Deleted in Liver Cancer-1 (DLC1), a member of the RhoGAP family of proteins, functions as a tumor suppressor in several cancers including breast cancer. However, its clinical relevance is unclear in breast cancer. In this study, expression of DLC1 was correlated with prognosis using publicly available breast cancer gene expression datasets and quantitative Reverse Transcription PCR in cohorts of Estrogen Receptor-positive (ER+) breast cancer. Mutation and methylation status of DLC1 were assessed in these datasets including The Cancer Genome Atlas (TCGA). To seek further insights in understanding the role of DLC1 in ER+ breast cancer, we developed a knock-in model of DLC1 in T47D breast cancer cells. Label-free global proteomic and TiO2 phosphopeptide enrichment assays were performed and validated using Western blotting. Here, we report that low expression of DLC1 correlates with poor prognosis in patients with ER+ breast cancer with further decrease in metastatic lesions. Analysis of the TCGA data showed that down regulation of DLC1 is not due to methylation or mutations. Stable knock-in of DLC1-full-length inhibits cell growth significantly in vitro compared to its control counterpart. 6726 phosphopeptides were quantified by phosphoproteomics analysis in both conditons, whereas 205 and 122 were unique to DLC1 knock-in and T47D-control cells, respectively. Pathway analysis using DAVID showed the top three significant clusters of differentially identified phosphopeptides involving cell-cell adhesion, mRNA processing and splicing, and transcription regulation. Decreased phosphorylation of epithelial cell transforming sequence 2 (ECT2) at the residue T359, critical for its active conformational change was validated. In conclusion, this data suggests that high expression of DLC1 reduces cell growth and is associated with favorable prognosis. Our results document an inverse relation between ECT2 phosphorylation and DLC1 expression, promising a novel strategy for treating ER+ breast cancer.
2018-10-04 | PXD008220 | Pride
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
Project description:Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal cancer. The mechanisms of the subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog by Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provides an explanation for bone preference in luminal breast cancer and new approaches for metastasis treatment.
2023-04-15 | GSE186230 | GEO
Project description:The overall goals are these experiments are to identify genes and pathways that are critical for hematopoietic stem cell functions during bone marrow regeneration after transplantation. We have found that loss of expression of p190-B RhoGAP, a negative regulator of RhoGTPase, enhances HSC long-term engraftment. Hence, we used microarray analysis to compare gene exprssion profile of WT and p190-B-/- HSC after transplantation.
2016-11-14 | GSE89794 | GEO
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.
2013-11-30 | GSE36102 | GEO
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
Project description:Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. We show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor-β (TGF-β)-induced EMT transcriptional signature. To further delineate the molecular mechanisms underlying the pro-migratory role of CdGAP in breast cancer cells, we searched for CdGAP interactors by performing a proteomic analysis using HEK293 cells overexpressing GFP-CdGAP. We found that CdGAP interacts with the adaptor Talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-β-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-β and Integrin/Talin signaling pathways.
2023-07-14 | PXD043376 | Pride
Project description:Most cancer deaths are due to metastatic dissemination to distant organs. Bone is the most frequently affected organ in metastatic prostate cancer and a major cause of prostate cancer deaths. Yet, our partial understanding of the molecular factors that drive bone metastasis has been a limiting factor for developing preventative and therapeutic strategies to improve patient survival and well-being. Although recent studies have uncovered molecular alterations that occur in prostate cancer metastasis, their functional relevance for bone metastasis is not well understood. Using genome-wide CRISPR activation and inhibition screens we have identified multiple drivers and suppressors of prostate cancer metastasis. Through functional validation, including innovative organ-on-a-chip invasion platform for studying bone tropism, our study identifies the transcriptional modulator, CITED2, as a novel driver of prostate cancer bone metastasis and uncovers multiple new potential molecular targets for bone metastatic disease.
2024-02-22 | GSE253815 | GEO