Ras signaling is a key determinant of metastatic dissemination and poor survival of luminal breast cancer patients
Menée à l'aide de modèles murins et de données extraites d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence le rôle joué par la signalisation Ras dans le processus métastatique d'un cancer de type luminal
Breast cancer (BC) is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic BC typically feature mutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in BC progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each pathway was activated singly or pairwise. All three oncogenes showed cooperation during primary tumor formation, but efficient dissemination was only dependent on Ras. In addition, transcriptional profiling demonstrated that Ras induced adenocarcinomas with molecular characteristics related to human basal-like and HER2+ tumors. In contrast, Ras combined with PIK3CAH1047R, an oncogenic mutant linked to ERα+/luminal BC in humans, induced metastatic luminal B-like tumors. Consistent with these data, elevated Ras signaling was associated with basal-like and HER2+ subtype tumors in humans, and showed a statistically significant negative association with ER-signaling across all BC. Despite this, there are luminal tumors with elevated Ras signaling. Importantly, when considered as a continuous variable, Ras pathway activation was strongly linked to reduced survival of patients with ERα+ disease independent of PI3K or Stat3 activation. Therefore, our studies suggest that Ras activation is a key determinant for dissemination and poor prognosis of ERα+/luminal BC in humans, and hormone therapy supplemented with Ras-targeting agents may be beneficial for treating this aggressive subtype.