CDK16 is a vulnerable target for triple negative breast cancer therapy
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ABSTRACT:
PROVIDER: PRJNA784419 | ENA |
REPOSITORIES: ENA
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Project description:Background: CDK16 is an atypical PCTAIRE kinase, and its activity is dependent on Cyclin Y (CCNY) family. CCNYs have been reported to regulate mammary stem cell activity and mammary gland development, and CCNY plays an oncogenic role in a variety of cancers including breast cancer. However, whether CDK16 plays a role in breast cancer and whether CDK16 can be served as a therapeutic target for breast cancer remains unknown. Methods: TCGA/GEO database analysis and KM survival analysis were used to examine the mRNA expression and the clinical relevance of PFTAIRE and PCTAIRE kinases in breast cancer. The expression of CDK16 protein was determined by CPTAC dataset output and immunohistochemical analysis of breast cancer tissue microarray and immunoblot analysis of additional clinical samples. Knockdown and overexpression of CDK16 were mediated by shRNA and lentivirus vectors, respectively. Cell proliferation was assessed by colony formation and MTT analysis. The cell cycle and apoptosis were examined by FACS analysis. Wound-healing and trans-well invasion assay were conducted to test cell migration ability. The functions of CDK16 on tumorigenesis and metastasis were evaluated by cell line-derived xenograft, patient-derived organoid/xenograft, lung metastasis and systemic metastasis mouse models. RNA-sequencing analysis was performed to reveal the potential molecular mechanisms involved in the function of CDK16. Pharmacological inhibition of CDK16 was achieved by its inhibitor Rebastinib to further assess the anti-tumor effect of targeting CDK16. Results: CDK16 is highly expressed in breast cancer, especially in triple-negative breast cancer (TNBC). The elevated CDK16 expression is correlated with poor outcomes in breast cancer patients. CDK16 promotes the proliferation and migration of TNBC cells in vitro and tumorigenesis and metastasis of TNBC tumors in vivo. Both gene knockdown and pharmacological inhibition of CDK16 significantly repress tumor progression of TNBC. Mechanically, CDK16 not only regulates spindle formation by phosphorylating PRC1 at the T481 site, but also regulates the Rb-E2F pathway by phosphorylating Rb, which are essential for cell cycle progression and cell proliferation of tumor cells. Conclusion: CDK16 plays an oncogenic role in TNBC and can be served as a novel potential therapeutic target for TNBC.
2021-12-03 | GSE189758 | GEO
Project description:Analysis of human triple-negative breast cancer cells (TNBCs) which have high NF-kB activity. Proteins derived from NF-κB target genes might be molecular targets for cancer therapy. Results provide new insights into tumor proliferation mechanisms.
2015-02-20 | GSE56812 | GEO
Project description:Analysis of human triple-negative breast cancer cells (TNBCs) which have high NF-kB activity. Proteins derived from NF-κB target genes might be molecular targets for cancer therapy. Results provide new insights into tumor proliferation mechanisms. Exp. 1: Mock MDA-MB-436 cells vs. MDA-MB-436 cells infected with Adenovirus-IkBaSR; Exp. 2: MDA-MB-436 cells infected with Adenovirus-GFP vs. MDA-MB-436 cells infected with Adenovirus-IkBaSR.
2015-02-20 | E-GEOD-56812 | biostudies-arrayexpress
Project description:Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), Low density lipoprotein receptor-related protein 6 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of ï?¢-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer. 14 pretreatment non-triple negative breast tumors compare with 5 triple negative breast tumor.
2011-06-01 | E-GEOD-27447 | biostudies-arrayexpress
Project description:Purpose: To understand the underlying mechanisms of oncolytic virus therapy in breast cancer. Methods: The primary tumors of 4T1 in BALB/C mice were exstracted and analyzed by RNA-seq. Results: In consistent with previous studies, we found some anti-tumor factors were up-regulated. Interestingly, several immunosupressive genes were activited. Conclusion: Our study identified the intercellular and intracellular factors restricting the optimized oHSV efficacy and supported the rationally designed triple therapy for clinical translation.
2023-05-01 | GSE201760 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE21719: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (miRNA study) GSE21832: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (gene expression) Refer to individual Series
2010-12-31 | E-GEOD-21834 | biostudies-arrayexpress
Project description:Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti‐tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi‐omic single‐cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 triple‐negative breast cancer, but this did not result in a reduction of tumor growth. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment. This subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a higher Treg‐inducing potential compared to other migcDCs. To shift the cDC phenotype towards a T‐cell stimulatory phenotype, CD40 agonist therapy was administered in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg promoting CD81+migcDC1. Nonetheless, while Treg‐depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti‐tumor responses and therefore might not be beneficial for the treatment of triple‐negative breast cancer, though could still be of use to increase cDC numbers for autologous DC‐therapy.
2023-07-26 | GSE225539 | GEO
Project description:Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer
| PRJNA638951 | ENA
Project description:Breast cancer is genetically and clinically heterogeneous. Triple negative cancer (TNBC) is a subtype of breast cancer usually associated with poor outcome and lack of benefit from target therapy. A pathway analysis in a microarray study was performed using TNBC compared with non-triple negative breast cancer (non-TNBC). Overexpression of several Wnt pathway genes, such as frizzled homolog 7 (FZD7), Low density lipoprotein receptor-related protein 6 (LRP6) and transcription factor 7 (TCF7) has been observed in TNBC. Focus was given to the Wnt pathway receptor, FZD7. To validate its function, inhibition of FZD7 using FZD7shRNA was carried out. Notably decreased cell proliferation, suppressed invasiveness and colony formation in triple negative MDA-MB-231 and BT-20 cells were observed. Mechanism study indicated that these effects occurred through silencing the canonical Wnt signaling pathway, as evidenced by loss of nuclear accumulation of beta-catenin and decreased transcriptional activity of TCF7. In vivo study revealed that FZD7shRNA significantly suppressed the tumor formation in xenotransplation mice due to decrease cell proliferation. Our finding suggests that FZD7 involved canonical Wnt signaling pathway is essential for tumorigenesis of TNBC. Thus, FZD7 may be a biomarker and a potential therapeutic target for triple negative breast cancer.
2011-06-01 | GSE27447 | GEO
Project description:The goal of this work was to identify all estrogen receptor beta target genes using RNA sequencing in MDA-MB-468 triple negative breast cancer cells engineered with inducible expression of full length estrogen receptor beta.
2015-08-12 | GSE71960 | GEO