Breast cancer (BC) is one of the commonest leading causes of death in females worldwide. Although survival rates for most subtypes of BC have improved due to advances in therapies and systemic treatment, triple negative breast cancers (TNBC) still have poor prognosis and limited treatment choices. Accounting for 15â20% of all breast cancer cases, TNBCs are more prevalent in African and carriers of BRCA germline mutations. Only 20% of TNBC patients respond well to standard therapy while the majority develop lethal metastatic disease. Efforts to decipher the complexity of TNBC have led to identification of six distinct molecular subtypes. This molecular subtyping may redefine the treatment options available through the identification of new molecular targets. The aim of this project is to investigate the role of the E3 ubiquitin ligase, RNF144B, in TNBC. RNF144B has a critical role in endometrial cancer cell proliferation, but only in the absence of hormonal stimulation. This role of ERÎ± mediated growth response suggested that RNF144B activity may have importance in TNBC. First, we investigated at RNF144B gene expression and found no specific pattern according to BC subtype. Interestingly, we found that RNF144B protein is highly expressed in TNBC cells but not other subtypes. To test RNF144B function, we used gene silencing. We found that after silencing RNF144B, MDA-MB-468 cell growth was significantly reduced. To identify possible substrates of RNF144B that might mediate its effect, we performed unbiased proteomic analysis after silencing RNF144B. Surprisingly, we found that the most prominent changes were in metabolic pathways, particularly in glycolysis and respiration . Increased glycolysis is a hall mark of cancer cell energy metabolism. Accordingly, this study identifies a critical role of RNF144B in TNBC is to increase glycolytic protein expression. Thus, inhibiting RNF144B may be a potential way to target TNBC metabolism and reduce proliferation.
|Date of Award
|31 Dec 2022
- The University of Manchester
|Andrew Gilmore (Supervisor) & Caroline Milner (Supervisor)