ESSENTIAL ROLE OF B-CELL LYMPHOMA-9 IN HUMAN BREAST DUCTAL CARCINOMA IN SITU PROGRESSION TO INVASIVE BREAST CANCER
Elsarraj, Hanan Sataa
University of Kansas
Pathology & Laboratory Medicine
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B-cell lymphoma-9 (BCL9) is a recently identified co-activator of -catenin mediated transcription. BCL9 has been shown to promote tumor metastasis in multiple myeloma and colon carcinoma. However, BCL9’s role in a switch from non-invasive to invasive cancers has not been recognized. By utilizing two unique in vivo models of human non-invasive to invasive breast cancers, tandem ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) and mouse-intraductal models, we have shown for the first time that BCL9 may be an important molecular switch in the malignant transition of at least a subset of non-invasive cancers by enhancing canonical WNT signaling and promotion of epithelial-mesenchymal transition (EMT). Analysis of RNA and protein at distinct stages of DCIS to IDC using both models showed BCL9 up-regulation to be associated with DCIS transition to IDC. In vivo silencing of BCL9 led to inhibition of DCIS invasion and reversal of EMT. Reverse phase protein analysis (RPPA)on DCIS cell lines Knockdown (KD) BCL9 vs. control indicated that BCL9 KD showed decreased expression of a number of genes in the EGFR signaling pathway, including p-EGFR, p-HER2, p-STAT3, and p-Src. In addition, BCL9 was evaluated as a biomarker of DCIS risk of recurrence. Analysis of 28 DCIS patients revealed high nuclear BCL9 expression to be associated with pathologic characteristics known to be correlated with an increased risk for recurrence: ER and PR negative, high nuclear grade, and HER2 positive (p <0.05). Analysis of the TCGA database showed BCL9 to be highly amplified in many cancers including breast, bladder and liver. Furthermore, BCL9 was amplified in a significantly higher proportion of invasive basal breast cancers compared to other subtypes. We conclude that BCL9 plays a key role in the malignant transition of a subset of non-invasive breast cancers and may promote invasion through enhancement of canonical WNT, EGFR and STAT3 signaling. The data also support that BCL9 is a potential biomarker to identify the risk of recurrence in DCIS patients.
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