Date of Award

9-20-2024

Publication Type

Thesis

Degree Name

M.Sc.

Department

Biological Sciences

Keywords

breast cancer;cancer;CDK inhibitors;cell cycle

Supervisor

Lisa Porter

Abstract

Breast cancer is the second most common cancer worldwide and the most common cancer among women, excluding non-melanoma skin cancers. The most common subtype of breast cancer is estrogen receptor-positive (ER+). Treatment for this subtype relies on the suppression of estrogen production or targeting ER directly through hormone therapy. Although hormone therapy remains the staple therapy for ER+ breast cancer, acquired resistance has remained a large challenge. Cyclin-dependent kinase (CDK) 4/6 inhibitors which inhibit the proliferation of ER+ breast cancer, have emerged as a powerful therapy significantly increasing progression free survival. However, resistance to CDK4/6 inhibitors remains a concern, and current research focuses on how patients develop this resistance. Data has emerged that demonstrates a role for late G1 and S cyclins and CDKs in CDK4/6 inhibitor resistance; however, current CDK inhibitor therapies don’t consider cyclin-like proteins such as Spy1. Spy1 can bind and activate CDK1/2 and promote proliferation even in the presence of DNA damage, overriding checkpoints and increasing cancer susceptibility. Spy1 has been shown to be significantly elevated in many cancers, including breast cancer. Using in vitro ER+ breast cancer model (MCF7) and data mining approaches, this study aimed to determine if Spy1 can drive resistance to CDK 4/6 inhibitors in ER+ breast cancer. It was found that Spy1 levels transiently increase following treatment with a CDK4/6 inhibitor and remain elevated in resistance models. This work supports evidence that Spy1 overexpression can override CDK4/6 inhibition. These results could provide further guidance about how CDK 4/6 inhibitor resistance is driven, ultimately to the development of new novel therapies for this patient population.

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