Abstract
Breast cancer is stratified into four distinct clinical subtypes, using three key biomarkers (Her2/Neu gene status, Estrogen and Progesterone receptor status). However, each subtype is a heterogeneous group, displaying significant variation in survival rates and treatment response. New biomarkers are required to provide more precise stratification of breast cancer cohorts to inform personalised treatment options/predict outcomes. Tip60 is a member of the MYST sub-family of histone acetyltransferases (HATs), and is directly involved in genome maintenance, gene regulation and DNA damage response/repair pathways (key chemotherapeutic influencing mechanisms). We aimed to determine if quantifying Tip60 staining patterns improved breast cancer stratification. We defined Tip60 protein in vivo, quantifying location (cytoplasmic, nuclear), percent of cells and staining intensity in a breast cancer tissue microarray (n = 337). A significant association of specific Tip60 staining patterns with breast cancer subtype, ER or PR status and Tumour grade was found. Importantly, low Tip60 mRNA expression correlated with poor overall survival and relapse free survival. We found Tip60 is a biomarker able to stratify breast cancer patients, and low Tip60 expression is a significant risk factor indicating a higher chance of disease reoccurrence. This work highlights Tip60 regulation as a key factor influencing the development of breast cancer.
Highlights
Modifications to histones regulate chromatin structure by opening or closing chromatin
Total mRNA was extracted with Tri Reagent (Sigma) as per manufacturer’s instructions. cDNA was synthesized from the extracted mRNA using SuperScript (Life Technologies) as per manufacturer’s instructions
Exploring if the variable gene expression observed resulted in changes to protein expression, Tip[60] protein was undetectable (Fig. 1B)
Summary
Modifications to histones (acetylation, methylation, phosphorylation) regulate chromatin structure by opening or closing chromatin. Within the MYST family the importance of Tip[60] is highlighted, as a Tip[60] knockout is lethal[12,13] This essential role for Tip[60] is further demonstrated in cancer cells, where down-regulation results in cell death[7,13,14]. Tip[60] has many diverse substrates, which is reflected in its diverse role in cellular processes These include DNA damage response, the cell cycle, apoptosis, signalling and transcriptional regulation[6,9,15,16]. A significant reduction in Tip[60] protein and mRNA expression has been found in several other cancers[3,6,7,9,10,16,18,19,20,21,22,23] We report the value of quantifying Tip[60] levels for the stratification of breast cancer
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