Abstract 2139: Wild type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL8 secretion via JAK2 activation
Authors: Zheng Ze-Yi , Bu Wen , Tian Lin , Fan Cheng , Gao Xia , Yu Cuijuan , Jun Liu , Zhang Xiaomei , Liao Yi-Hua , Li Yi , Lewis Michael T. , Edwards Dean , Hilsenbeck Susan G. , Medina Daniel , Zwaka Thomas P. , Perou Charles M. , Creighton Chad J. , Zhang Xiang , Chang Eric C. 
Published: August 2015

“Basal-like” breast cancer (BLBC) is the most aggressive breast cancer subtype, with a 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, and oncogenic mutations in the RAS genes, and 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, partly via promoter demethylation, but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, while overexpression enhances these processes even in preinvasive BLBC cells. In contrast, repressing N-RAS expression does not affect growth and transforming activities of breast cancer cells of other subtypes. We identified N-Ras-responsive genes, most of which encode chemokines, 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. Thus N-Ras drives BLBC by promoting transformation in epithelial cells, which in turn remodels the tumor microenvironment to create a proinvasive state.

These results illustrate an N-Ras-dependent convergence between the growth factor and cytokine pathways to enable efficient transformation of epithelial cells, which then orchestrate the remodeling of the tumor microenvironment. 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: Ze-Yi Zheng, Wen Bu, Lin Tian, Cheng Fan, Xia Gao, Cuijuan Yu, Liu Jun, Xiaomei Zhang, Yi-Hua Liao, Yi Li, Michael T. Lewis, Dean Edwards, Susan G. Hilsenbeck, Daniel Medina, Thomas P. Zwaka, Charles M. Perou, Chad J. Creighton, Xiang Zhang, Eric C. Chang. 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 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2139. doi:10.1158/1538-7445.AM2015-2139