Abstract 2139: Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation

"Basal-like" breast cancer (BLBC) is a very aggressive subtype of breast cancer. BLBC has very poor prognosis — median time to distant recurrence is just 2.6 years vs. 5 years overall, and survival time from diagnosis of distant metastatic disease is 9 months vs. 22 months. BLBC tumors usually do not express ER, Her2, or progesterone receptor. As such, they cannot be treated by the current targeted therapies, which target these molecules. What drive the formation and progression of BLBCs is largely unclear. Ras GTPases are best known for mediating growth factor signaling. Oncogenic mutations in the RAS genes, K-RAS in particular, are found in more than 30% of human tumors. Surprisingly, oncogenic RAS mutations are rare in breast cancer. However, we found that wild-type N-RAS is overexpressed in BLBCs, possibly partly via promoter demethylation, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpressing it enhances these processes even in preinvasive BLBC cells. In contrast, in breast cancer cells of other subtypes, repressing N-RAS expression does not affect growth and transforming activities. We identified N-Ras-responsive genes, most of which encode chemokines and cytokines, e.g., IL8. High expression levels of these N-Ras-responsive genes as well as of N-RAS itself in tumors correlate with poor patient outcome. N-Ras, but not K-Ras, induces IL8 by binding and activating the cytoplasmic pool of JAK2; IL8 then acts on both the cancer cells and stromal fibroblasts. In conclusion, N-Ras drives BLBC by promoting transformation in epithelial cells, which may in turn remodel the tumor microenvironment to create a proinvasive state. Although oncogenic mutations affecting RAS are common in many other human cancers, tumorigenesis in an important subset of breast cancers is driven instead by increasing activity of wild-type N-Ras. Thus, to fully assess the impact of Ras on tumorigenesis, the role of wild-type as well as mutant Ras proteins must be carefully examined. Citation Format: Zheng Z-Y, Bu W, Tian L, Fan C, Gao X, Zhang X, Yu C, Wang H, Liao Y-H, Li Y, Lewis MT, Edwards D, Zwaka TP, Hilsenbeck SG, Medina D, Perou CM, Creighton CJ, Zhang XH, Chang EC. Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-06-11.