Effect of nutritive conditions, adhesion and EMT on transcriptional profile of HMECs transduced by an oncogene RAS and SNAI1, SNAI2 or SNAI3

ABSTRACT: Oncogenic stress induces a global disturbance of cellular homeostasis and subsequently triggers the activation of tumour suppressor pathways. Energy capacity loss, redox state imbalance, and biosynthetic deficiency constitute the primary signals activating safeguard mechanisms, culminating in levels of stress that should not be compatible with infinite proliferative capacities of tumour initiating cells (TIC)s or cancer stem cells (CSC)s. Here, we show that the control of the glucocorticoid response by embryonic factors involved in mammary stemness5, 6 enables basal breast CSCs to not be faced with this oncogenic stress. The glucocorticoid response is thus correlated with stemness properties in basal breast cancers and is required for neoplastic transformation of mammary progenitors. This effect does not rely on hijacking tumour suppressor pathways, but on homeostatic buffering capacity. Through extensive analysis of homeostatic parameters and metabolic profiling, we show that the glucocorticoid response in mammary CSCs limits the “Warburg effect”, the ability of an oncogene to drive glucose fermentation in the presence of oxygen. The glucocorticoid response dampens glycolytic flow and maintains respiratory capacity resulting in reduction of mitochondria energisation. This enables CSCs to sustain carbon and nitrogen flows generated via glycolysis and the tricarboxylic acid cycle (TCA), required for homeostasis and anabolism maintenance. Overall, our results reveal the role of hormonal control of metabolic reprogramming in a CSC in rendering the cell permissive to oncogenic activity. Immortalized human mammary epithelial cells (HMEC-hTERT cells) were infected with SNAIL retroviral expression constructs and an inducible form of RAS G12V. The gene expression profiles of the resulting cell lines, cultured in standard conditions, in limited nutrient supply or after plating them 16h in low-adherent (LA) conditions, were performed.

ORGANISM(S): Homo sapiens

SUBMITTER: Anne Wierinckx 

PROVIDER: E-GEOD-56164 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress