Cyclin D1, cancer progression, and opportunities in cancer treatment

Abstract

Mammalian cells encode three D cyclins (D1, D2 and D3) that coordinately function as allosteric regulators of cyclin dependent kinase 4 and 6 (CDK4/CDK6) to regulate cell cycle transition from G1 to S phase. Cyclin expression, accumulation and degradation, as well as assembly and activation of CDK4/CDK6 are governed by growth factor stimulation. Cyclin D1 is more frequently dysregulated than cyclins D2 or D3 in human cancers and as such it has been more extensively characterized. Overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signaling, bypass of key cellular checkpoints and ultimately neoplastic growth. This review discusses cyclin D1 transcriptional, translational, posttranslational regulation, and its biological function with a particular focus on the mechanisms that result in its dysregulation in human cancers.

LncRNA ABHD11‐AS1 promotes the development of endometrial carcinoma by targeting cyclin D1

“…Cyclin D1, one of the three mammalian cyclin D molecules, is the most well‐studied cyclin. Cyclin D1 is more frequently differentially expressed in human cancers than cyclin D2 or D3, is an important mediator of cancer initiation, development and metastasis and is associated with poor prognosis . Cyclin D1 is widely involved in cancer: cyclin D1 promotes cell proliferation in colorectal cancer; EMSY and CCND1 work together to contribute to the pathogenesis of lung cancer; extracellular adenosine induces G1 cell cycle arrest via the cyclin D1/CDK4 pathway in ovarian cancer; the EGFR/PI3K/Akt/cyclin D1 signalling pathway may play a key role in cholesteatoma; microRNA‐338‐3p can bind cyclin D1 and mediates hepatocyte proliferation in hepatocellular carcinoma; P16/cyclin D1/CDK4 signalling pathway alterations may affect epithelial cell proliferation and apoptosis in gallbladder carcinoma, even during initiation; and β‐catenin is involved in pancreatic cancer carcinogenesis and metastasis by up‐regulating cyclin D1 …”

Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration‐resistant prostate cancer (CRPC)

“…We also made the important observation that CDK4/CDK6 inhibitors were effective at inhibiting the enzalutamide‐resistant growth of LNCaP cells. The CCND1 pathway is commonly dysregulated in cancers and has long been thought to contribute to prostate cancer progression. 26 We interrogated the publicly available Neuroendocrine Prostate Cancer data set on the cBioPortal for Cancer Genomics for alterations in CCND1 pathway genes (Supporting Fig.…”

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Conversely, expression of plasmids encoding either dominant negative MAPK (p41 MAPKi ) or dominant-negatives of ETS activation, antagonized MAPK-dependent induction of Cyclin D1 promoter activity. In summary Ets2 plays critical role in Cyclin D1 induction in response to mitogenic pathways mediated by Ras and MAPK (49, 126–130). …”