Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers

Abstract

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 diffi cult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo . Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition 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. SIGNIFICANCE:The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating 7(2);

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

“…Ras activation was associated with increased phosphorylation of ERK1/2 and transcripts for Ras target genes and some pathway mediators, but variable rPrl transgene expression and reduced canonical downstream mediators of PRL signaling. These findings coincide with recent reports that elevated Ras signaling drives many clinical luminal B cancers, and is associated with a poor prognosis (Olsen et al, 2017;Wright et al, 2015) . In contrast to Kras-activated tumors, preneoplastic mammary glands maintained constitutive expression of rPrl and displayed elevated transcripts for cytokines associated with pro-tumor myeloid populations.…”

“…The low rate of somatic mutations and predicted low tumor infiltrating lymphocytes in NRL-PRL tumors mimic the relative immune silence of clinical luminal breast cancers (Dieci et al, 2016;Luen et al, 2016;Vonderheide et al, 2017) . Although the frequency of RAS mutations is relatively low in human breast cancer (<5%) (Cancer Genome Atlas Network, 2012; Curtis et al, 2012) , recent studies have revealed that a high proportion of luminal B ER+ breast cancers display elevated Ras pathway activity as a result of reduced expression or somatic loss of RasGAP tumor suppressors (Griffith et al, 2018;Olsen et al, 2017;Wright et al, 2015) . RAS itself has been an elusive therapeutic target (McCormick, 2015;Tran et al, 2016) .…”

RAS Proteins and Their Regulators in Human Disease

“…These diseases have been notable for the absence of frequent mutations in RAS genes themselves. In prostate cancer, loss of DAB2IP expression leads to coordinated activation of RAS and nuclear factor κB (NF-κB) (Min et al, 2010), whereas in luminal B breast cancers, simultaneous loss of DAB2IP and RASAL2 drives invasion, EMT, and metastasis (Olsen et al, 2016). …”

Metastatic tumor cells – genotypes and phenotypes

“…Moreover, multiple signaling pathways may be required to cooperate at critical steps of metastasis. Transcriptional analysis of different subtypes of breast cancer revealed a specific correlation between the loss of expression of RasGAP tumor suppressor genes and aggressive luminal B breast tumors (Olsen et al, 2017). Functionally, these RasGAP genes cooperatively regulate RAS and NF-kB signaling that enhance metastatic features such as invasion and EMT, respectively.…”