Luminal breast cancers are typically estrogen receptor positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here we identify a bi-functional RasGAP tumor suppressor that is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly inactivated in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, Ras and NF-kappa B through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, while the cooperative effects on Ras drive invasion, NF-κB activation triggers EMT and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.
- Received May 5, 2016.
- Revision received December 9, 2016.
- Accepted December 12, 2016.
- Copyright ©2016, American Association for Cancer Research.