PTHrP regulates fatty acid metabolism via novel lncRNA in breast cancer initiation and progression models
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ABSTRACT:
PROVIDER: PRJNA937747 | ENA |
REPOSITORIES: ENA
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Project description:The 5-year survival rate for women with metastatic breast cancer is 29%. Potential biomarkers identification is important for new therapeutic treatment in affected patients. Previous studies have shown that Parathyroid hormone-related peptide (PTHrP) plays a critical role in breast cancer growth and metastasis. The aim of our study was to use a genetically modified breast cancer mouse model to precisely examine the role of PTHrP from early primary breast cancer initiation to late progression. We identified a novel lncRNA, a new target for fatty acid metabolism that can be regulated by PTHrP in our unique mouse breast cancer model. We confirmed that a potential human lncRNA, OLMALINC, plays a similar role in fatty acid metabolism that can be regulated by PTHrP. Therefore, we validated our mouse finding in the human breast cancer cell lines. Genetically engineered mouse models provide valuable tools to study the molecular progression for breast cancer metastasis.
2023-12-30 | GSE225877 | GEO
Project description:Parathyroid hormone-related peptide (PTHrP) is the primary cause of malignancy-associated hypercalcemia (MAH). We previously showed that PTHrP ablation, in the MMTV-PyMT murine model of breast cancer (BC) progression, can dramatically prolong tumor latency, slow tumor growth, and prevent metastatic spread. However, the signaling mechanisms using lineage tracing have not yet been carefully analyzed. Here, we generated Pthrpflox/flox; Cre+ mT/mG mice (KO) and Pthrpwt/wt; Cre+ mT/mG tumor mice (WT) to examine the signaling pathways under the control of PTHrP from the early to late stages of tumorigenesis. GFP+ mammary epithelial cells were further enriched for subsequent RNA sequencing (RNAseq) analyses. We observed significant upregulation of cell cycle signaling and fatty acid metabolism in PTHrP WT tumors, which are linked to tumor initiation and progression. Next, we observed that the expression levels of a novel lncRNA, GM50337, along with stearoyl-Coenzyme A desaturase 1 (Scd1) are significantly upregulated in PTHrP WT but not in KO tumors. We further validated a potential human orthologue lncRNA, OLMALINC, together with SCD1 that can be regulated via PTHrP in human BC cell lines. In conclusion, these novel findings could be used to develop targeted strategies for the treatment of BC and its metastatic complications.
| S-EPMC10417726 | biostudies-literature
Project description:Analysis of Gene Expression in PTHrP-/- Mammary Buds Supports a Role for BMP Signaling and MMP2 in the Initiation of Ductal Morphogenesis. Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP’s effects on mesenchymal cells, we profiled gene expression in WT and PTHrP-/- mammary buds, and in WT and K14-PTHrP ventral skin, at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds. Five experimental groups (WT mammary buds, PTHrP-/- mammary buds, WT ventral skin, K14WT ventral skin, K14-PTHrP ventral skin). Three replicates in each group. Differentially expressed genes are listed in the following supplementary files: GSE17654_List1a-Higher_in_KO_Buds_than_WT_Buds.txt GSE17654_List1b-Lower_in_KO_Buds_than_WT_Buds.txt GSE17654_List2a-Higher_in_WT_Skin_than_WT_Buds.txt GSE17654_List2b-Lower_in_WT_Skin_than_WT_Buds.txt
2009-08-15 | E-GEOD-17654 | biostudies-arrayexpress
Project description:Analysis of Gene Expression in PTHrP-/- Mammary Buds Supports a Role for BMP Signaling and MMP2 in the Initiation of Ductal Morphogenesis. Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP’s effects on mesenchymal cells, we profiled gene expression in WT and PTHrP-/- mammary buds, and in WT and K14-PTHrP ventral skin, at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds.
2009-08-15 | GSE17654 | GEO
Project description:Lack of PTH/PTHrP receptor in PTHrP+ dental follicle cells causes a cell fate shift and premature differentiation. Here, we set out to reveal the transcriptome change induced by deficiency in PTH/PTHrP receptor in PTHrP+ dental follicle cells
2018-08-01 | GSE117936 | GEO
Project description:A PTHrP construct expressing full-length secreted PTHrP (-36-139aa) was stably expressed in MCF7 cells. The goal of the study was to determine the gene targets of PTHrP in human MCF7 breast cancer cells.
2018-05-30 | GSE110713 | GEO
Project description:Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are involved in cachexia associated with chronic kidney disease and cancer respectively. Tumor-derived PTHrP triggers adipose tissue browning and thereby leads to wasting of fat tissue in tumor-bearing mice. Similarly, elevated in 5/6 nephrectomized mice, PTH stimulates adipose tissue browning and wasting. Mice lacking the PTH/PTHrP receptor in their fat tissue are resistant to wasting of both adipose tissue and skeletal muscle. Therefore, the PTH/PTHrP signaling in adipocytes should activate various pathways that contribute to hypermetabolism and muscle wasting.
2015-12-01 | GSE74082 | GEO
Project description:Parathyroid hormone-related protein (PTHrP) is overexpressed in many cancer types. This secretory protein can induce hypercalcaemia of malignancy by mimicking the action of calcium-regulating parathyroid hormone (PTH). PTHrP may also be involved in the regulation of migration, invasion, proliferation and apoptosis. It can either stimulate signal cascades, such as the cAMP pathway, or act on not yet defined targets in the nucleus. In this study, we analyzed the effect of PTHrP-specific siRNA on gene expression in MDA-MB-231 breast cancer cells. MDA-MB-231 cells were either transfected with the PTHrP-specific siRNA (siPTHrP) or a control siRNA (siLuc). Differences in gene expression pattern in siPTHrP- vs. siLuc-treated cells were measured by microarray analysis. More than 200 differentially expressed genes were found. Some of these genes have important functions in carcinogenesis. Keywords: siRNA knock-down analysis
2006-02-25 | GSE4292 | GEO
Project description:PTHrP is abundantly expressed by dental follicle cells. We set out to reveal single cell profiles of FACS-sorted PTHrP-mCherry+ cells isolated from the mandible.
2018-09-19 | GSE120108 | GEO