Defining a Novel Pathway Promoting Tumor Progression and Metastasis

Breast cancer (BC) is the second leading cause of cancer-related death in women. A significant proportion of BC patients develop recurrent disease that progresses to the metastatic stage and becomes refractory to therapies. Our goals are to define what drives metastatic progression and to develop novel therapies that would eliminate the mortality associated with metastatic BC.

The interaction of tumor cells with tumor microenvironment plays a key role in cancer progression, response to therapy, and progression to metastatic disease. The anti-inflammatory TGF-beta and pro-inflammatory TNF and IL1 cytokines are abundant in the tumor microenvironment and promote tumor invasion and metastatic progression. Our laboratory has shown that TAK1 is essential for TGF-beta promotion of metastasis by stimulating expression of pro-invasive, pro-angiogenic, and pro-survival factors including matrix metalloproteinase 9 (MMP9), VEGF, and cellular inhibitors of apoptosis (cIAPs). To define the molecular targets for anti-cancer therapy, we undertook a rigorous investigation of how TGF-beta and TNF/IL1 cytokines cooperate in the regulation of MMP9 and other pro-metastatic factors.

The study assessed how genetic modulation of signal transduction pathways by RNA interference and dominant-negative approaches would impact the biochemical markers of TAK1 responses and tumorigenic capacity of tumor cells. Knockdown of signaling components of cytokine pathways revealed major signaling molecules that play essential role in the regulation of MMP9 and other pro-metastatic factors. To complement this genetic analysis, we explored how experimental compounds targeting critical kinases in the pathways would impact tumor invasive and metastatic capacity. Our preclinical studies identified novel strategies for treatment of metastatic breast cancers, especially triple-negative breast cancers that are frequently irresponsive to current therapeutic regiments. We will present details of these novel findings and outline our recent advancements on the role of TAK1 in breast cancer.