Amirkhani Namagerdi, Asadoor (2023) Reactivation of the Retinoblastoma family of proteins by Cyclin-dependent kinase inhibitors in Canine Mammary Tumors. [Tesi di dottorato]

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Abstract

Abstract Comparative Oncology refers to the discipline that integrates the naturally occurring cancers seen in veterinary patients into more general studies of cancer biology and therapy. This includes the study of cancer pathogenesis (i.e., the study of cancer-associated genes and proteins) and the study of new treatment options for the management of cancer. This approach provides novel opportunities for current and future veterinary and human cancer patients. Although several veterinary species, including cats, horses, and ferrets, develop cancers that are of comparative interest, the majority of both the scientific and clinical effort has thus far focused on the dog. The partially overlapping transcriptome and proteome of metastatic canine mammary tumors (CMT) and human breast cancer (HBC) suggests that there is underlying comparable evidence that metastatic canine carcinomas are the suitable translational model for human breast tumors which could be used to determine prognostic and predictive molecular signatures and identify therapeutic targets. The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in many human cancers and is aberrant in one-third of all breast cancers. RB regulates G1/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. It is known that pRb can be inactivated by various mechanisms including genetic mutations and phosphorylation. The most important target of the retinoblastoma (RB) protein family members (p105, p107and p130) is the E2F family of transcription factors, which control the expression of genes that mediate G1-S transition. Together, these proteins are often referred to as pocket proteins. At the transition to S-phase, cyclin/CDK complexes phosphorylate the pocket proteins and transcription of E2F target genes proceeds through the S phase. Cell-cycle progression is mediated by cyclin-dependent kinases (CDKs) and their regulatory cyclin subunits. Overexpression and/or dysfunction of CDKs or cyclins has been reported in a very large number of human cancers and other diverse pathologies. These protein kinases are considered valuable therapeutic targets for drug development. CDK4/6 inhibitors like palbociclib inhibit CDK4/6-mediated phosphorylation of RB. In this study, we showed that Palbociclib inhibits pRb phosphorylation in the CMT primary cells that express CDK4, CDK6, and the Rb family of proteins independent of ER expression, in a dose and time-dependent manner. Moreover, it decreased CMT cell migration, spheroid formation, and colony formation. Our findings suggest that palbociclib as a CDK4/6 inhibitor can be a candidate for the treatment of CMTs.

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