GlucoDrop · Investigating glucocorticoids as regulators of lipid-mediated metastatic spreading of triple negative breast cancer

Triple negative breast cancer (TNBC) is the most aggressive and lethal breast cancer subtype, but it lacks expression of the estrogen receptor, the canonical driver of breast cancer development and progression. This indicates that there may be other molecular drivers in this context. The glucocorticoid receptor (GR) is a candidate oncogenic factor in TNBC, that has been shown to support TNBC cell proliferation and metastatic spread. Therefore, GR antagonism may be a viable strategy to attenuate TNBC aggressiveness, however, the precise molecular mechanism of GR action in TNBC cells remains to be determined.Recent experiments performed in the host laboratory demonstrated that GR activation induced lipid droplet (LD) accumulation, and shifted the balance of the metabolic mTOR signaling complexes, promoting mTORC2 activity, in breast cancer cells. Given that mTORC2 is a regulator of lipid metabolism, and has been implicated in the aggressiveness of TNBC, these observations are compelling and may be linked. Therefore, this project aims to investigate the role of these changes in regulating TNBC metastatic spread, by determining the precise molecular mechanism to explain these effects.To achieve these aims, I will firstly determine the interactome of the GR-induced mTORC2 and investigate the consequences of these specific interactions in TNBC cells, including on LD accumulation. Subsequently, I will use patient-derived organoids to determine the contribution of the GR-induced LDs to TNBC metastatic capacity and oncogenic phenotypes.The successful completion of this project will answer key questions relating to the role of GR as an oncogenic factor in TNBC, and define a novel interaction between the GR and mTORC2 signaling axes, which has never been described. In the long term, these findings could facilitate the design and implementation of novel therapeutic options for TNBC, to improve the outcomes for patients diagnosed with this aggressive breast cancer subtype.