Department of Pathology and Laboratory Medicine
University of Kansas Medical Center
Role of BCL9 in STAT3 Signaling and DCIS Invasive Progression (2015-2016)
The long-term goal of our studies is finding therapeutic strategies for prevention of breast cancer noninvasive to invasive progression. Human ductal carcinoma in situ (DCIS) is the most common type of noninvasive breast cancers. The five-year survival for women diagnosed with non-invasive DCIS is 98% while, the five-year survival plummets to 27.1% for breast cancers that have become invasive and have spread to distant sites [also referred to as invasive ductal carcinoma (IDC)]. Molecular profiling of breast cancer at distinct stages of DCIS to IDC using our in vivo DCIS progression models led to the identification of B cell lymphoma-9 (BCL9). Prior to our studies, the specific role of BCL9 in breast cancer had not been demonstrated. Analysis of TCGA database showed amplification and mRNA upregulation in BCL9 in 26% of invasive breast cancers. Interestingly, BCL9 amplification was significantly higher in basal breast cancers (BLBC) suggesting that BCL9 may underlie the development of BLBC. BLBC are the most aggressive forms of breast cancers and are associated with significantly lower overall survival and highest rate of metastasis. Our studies showed that in vivo silencing of BCL9 led to inhibition of DCIS invasion and reversal of epithelialmesenchymal transition (EMT). Our laboratory as well as others previously demonstrated a direct binding interaction between BCL9 and β-catenin and showed suppression of β-catenin-mediated transcription by BCL9 knockdown. However, our lab is the first to show a direct binding interaction between BCL9 and STAT3. We hypothesize that BCL9 promotes human non-invasive to IDC (basal like) transition by enhancement in the activity of STAT3 and canonical Wnt oncogenic signaling.
We propose the following two specific aims:
Specific Aim 1: Characterize the binding interactions between BCL9 and STAT3 by x-ray crystallography.
Specific Aim 2: Conduct fragment screening by Surface Plasmon Resonance (SPR) to Identify chemical compounds that interfere with the binding of BCL9 to STAT3.
Our studies could identify lead compound(s) that, by targeting BCL9/STAT3 binding interactions, serve as pharmacologic agents for prevention of breast cancer progression. There are currently no therapies designed specifically to target prevention of DCIS progression to invasive breast cancer, so identification of a specific therapy for this indication would represent an important advance in breast cancer treatment.