Dataset Information

CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling

ABSTRACT: Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.

SUBMITTER: Dr. Hee-Joo Choi

PROVIDER: S-SCDT-EMBOR-2019-48058V1 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Panax notoginseng saponins (PNS) are a commonly used traditional medicine to treat diabetes in China. Recent studies have confirmed their anti-diabetic effects, but the underlying mechanisms have remained unclear. The present study was designed to explore whether PNS decrease hyperglycemia by improving insulin sensitivity in skeletal muscle and to elucidate the molecular mechanisms. The anti-diabetic effects of PNS were analyzed in a skeletal myoblast cell line, C2C12, and in high fat diet-induced diabetic KKAy mice. C2C12 cells were treated with PNS (50, 100, and 200 μg·L-1 ) and examined for glucose uptake, cell viability and expression of components of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. KKAy mice were intraperitoneally injected with PNS (200 mg·kg-1 ) for 6 weeks. Body weight, blood glucose, serum insulin, serum lipid, glucose and insulin tolerance were measured to evaluate the anti-diabetic effects of PNS. Pathological changes, apoptosis and the PI3K-AKT signaling pathway were analyzed in KKAy skeletal muscle. PNS significantly increased insulin-induced glucose uptake, but did not affect the cell viability of C2C12 cells. In addition, PNS reduced blood glucose and serum insulin levels and improved glucose tolerance and insulin tolerance of KKAy mice. Pathological changes and apoptosis of skeletal muscle were relieved by PNS treatment. Moreover, PNS treatment enhanced expression of mRNA encoding IRS1 and GLUT4, as well as the protein expression of phosphorylated (p) -insulin receptor substrate 1 (IRS1), p-PI3K, p-AKT and glucose transporter type 4 (GLUT4) in C2C12 and KKAy mouse muscle. Collectively, these data indicate that PNS reduces hyperglycemia and insulin resistance through up-regulating GLUT4 expression and the IRS1-PI3K-AKT signaling pathway. Furthermore, PNS alleviated diabetes skeletal muscle pathological damage. Thus, our data suggest that PNS may be promising anti-diabetic compounds.

Dataset Information

CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets