Targeting Death Pathways for the Prevention of ER-negative Breast Tumors

Left Panel: Schema for the RAc/Trail experiment. MMTV-wnt transgenic mice will be treated with vehicle, RAc and/or TRAIL, as defined in the schematic above, for a period of one year. At the end of the study period, mice will be sacrificed and effectiveness of the RAc/TRAIL treatment in preventing ER-negative versus ER-positive tumors will be evaluated. Right Panel: H&E staining of mammary glands in normal and cancer cells after 5 months treatment with vehicle.

Recent studies suggest that overactivation of the Wnt pathway contributes to the pathogenesis of basal-like breast cancer, a subtype of estrogen receptor (ER)-negative breast cancer. This hormone-independent pathway leads to the nuclear localization of β-catenin where it forms a complex with T-cell factors or lymphoid enhancing factors (Tcf/Lef) and activates transcription of genes that drive proliferation.  In colon cancer, loss of the tumor suppressor gene adenomatous polyposis coli (APC) also results in nuclear localization of β-catenin.  Our collaborators have identified a chemopreventive regimen that selectively induces apoptosis in APC-deficient premalignant colon cells.  Initial treatment with retinyl acetate (RAc) in this regimen upregulates tumor necrosis-related apoptosis-inducing ligand (TRAIL) receptors.  When this is subsequently followed by treatment with TRAIL ligand, apoptosis is induced specifically in those premalignant cells with deregulated anti-apoptotic machinery.  Since loss of APC and constitutive activation of Wnt signaling both result in nuclear localization of β-catenin, we hypothesize that sequential treatment with RAc/TRAIL will induce apoptosis in Wnt-dependent premalignant breast epithelial cells.  To test this hypothesis, we are treating MMTV-Wnt1 transgenic mice which spontaneously develop both ER-positive and ER-negative mammary tumors with the RAc/TRAIL chemopreventive regimen.  This study will enable us to determine the effectiveness of this novel treatment in the prevention of ER-negative tumors.

Lab members working on this project:  

Karrie Wheatley, Ph.D., Jamal Hill, Senior Research Assistant and Yun Zhang, Senior Research Assistant.