Phospho-SAMHD1 as a potential prognostic biomarker for triple negative breast cancer patients Pubblico
Danelia, Diana (Spring 2021)
Published
Abstract
Triple negative breast cancer (TNBC) consists of a heterogeneous group of tumors characterized by a lack of estrogen and progesterone receptors, as well as lack of expression of the human epidermal growth factor receptor 2 (HER2) gene. Due to TNBC’s lack of drug- targetable receptors, treatment options are generally limited to chemotherapy and resection. Additionally, metastasis as well as survival after metastatic relapse has been found to be shorter compared to other breast cancer subtypes, making TNBC one of the more aggressive breast cancers. Because of this, understanding the molecular characteristics of TNBC and identifying biomarkers that could be used for prognostic information could significantly help improve patient care by allowing for tailored treatments that improve patient outcomes.
Many cancer cells exhibit impaired intracellular dNTP pool homeostasis, leading to rapid cellular proliferation, enhanced mutagenesis, and dysregulation of the cell cycle. Intracellular dNTP pools are regulated partly by sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) which acts as a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase. SAMHD1 has been found to have a role in restricting human immunodeficiency virus type 1 (HIV-1) and js also dysregulated in Aicardi Goutières syndrome (AGS) and cancers such as chronic lymphocytic leukemia (CLL). SAMHD1 has also been shown to have a role in promoting homologous recombination (HR) mediated DNA double strand break (DSB) repair independent of its dNTPase activity. Collectively, given SAMHD1’s importance across cancers, as well as its roles in maintaining genome integrity, this protein demonstrates potential as a prognostic biomarker for TNBC.
SAMHD1 activity is partly regulated in a phosphorylation dependent manner throughout the cell cycle. SAMHD1 is phosphorylated at the C-terminal Thr592 amino acid residue by cycling-dependent kinases 1 and 2 (CDKs) in preparation for S-phase DNA replication. This lowers the rate of dNTP hydrolysis, coinciding with an increase in intracellular dNTPs. We show that for TNBC patients, individuals with higher p-SAMHD1 expression demonstrate worse progression-free survival outcomes, likely due to more aggressive tumors as a result of dNTP pool imbalances from impaired SAMHD1 dNTPase activity from its phosphorylation.
Table of Contents
Chapter 1: Introduction 1
Chapter 2: Methods 3
Chapter 3: Results 5
Chapter 4: Discussion 7
Chapter 5: Figures 9
Chapter 6: References 19
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