Study reveals a novel target for the treatment of breast cancer
Image Caption: Treatment with the drug pimozide reduced tumor growth in a mouse model of breast cancer. Immunohistochemistry for phosphorylated (active) STAT5 and total STAT5 protein indicates that activation of STAT5 signaling is inhibited by pimozide treatment in vivo. Adapted from Mapes, et al. (Journal of Biological Chemistry 2018).
The proliferation and differentiation of the mammary gland is a process tightly controlled by hormones and growth factors. Dysregulation of the signaling pathways that orchestrate mammary gland development is frequently linked to the excessive, unchecked proliferation associated with breast cancer. The Bagchi lab previously discovered that CUZD1 is a mediator of the STAT5 and epidermal growth factor (EGF) family signaling pathways that promote proliferation of mammary epithelial cells (Mapes, et al., PLOS Genetics, 2017). The current study presents CUZD1 as a potential therapeutic drug target in breast cancers in which the STAT5 pathway plays a major role.
Mammary epithelial cells modified to express high levels of CUZD1 displayed increased proliferation and formed large tumors when introduced into the mammary glands of mice. High levels of activated STAT5 were present in these tumors, in addition to increased signaling through the EGF family pathway. This model allowed researchers in the Bagchi lab to investigate the effects of a STAT5 inhibitor on the growth of mammary gland tumors. This study repurposed a previously FDA-approved antipsychotic drug, pimozide, known to inhibit the activating phosphorylation of STAT5. Mice treated with pimozide showed a significant reduction in growth of Cuzd1-overexpressing mammary tumors. Analysis of the tissue from these tumors showed that this growth reduction was accompanied by suppression of STAT5 activation and of the EGF signaling pathway. Collectively, these findings indicate that blockade of the STAT5 signaling pathway downstream of CUZD1 offers a potential strategy for treating breast tumors that rely on these pathways for growth and survival.
This work was supported by the Eunice Kennedy Shriver NICHD/National Institutes of Health through cooperative agreement U54 HD055787 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research.
April 06, 2018.