Novel CXCR3/CXCR7-Directed Biological Antagonist for Inhibition of Breast Cancer Progression.

摘要

Docetaxel, a well-established anti-mitotic agent, has been shown in large clinical trials to improve survival and is arguably the standard of care for breast cancer (BrCa) that no longer respond to other therapies. Unfortunately, docetaxel has a number of serious side effects. Therapies that simultaneously prevent BrCa progression and improve docetaxel efficacy are greatly needed. To this end, the numerous anti-apoptotic mechanisms employed by BrCa cells to survive serum-free environments or apoptosis-inducing agents are not entirely known. Chemokines support BrCa progression and cell survival; BrCa cells express CXCR3, CXCR4, and CXCR7, which bind CXCL11 and/or CXCL12. We created a mutant CXCR3/CXCR7 ligand immunoglobulin fusion protein (mut-CXCL11-Ig) that lacks immunogenic, glycosaminoglycan (GAG)-binding sites but retains the ability to bind, but not activate CXCR3 and CXCR7 receptors. While we had difficulty scaling-up the production of the mut-CXCL11-Ig candidate, we report we have developed a new expression system for production and future animal studies. We also report CXCR3/CXCR4/CXCR7 expression are higher during the G2 phase of BrCa cell cycle, supporting proliferation. CXCL11-Ig reduces chemokine receptor expression, increases docetaxel-driven apoptosis, and reduces CXCL12-dependent cell growth. These studies provide important and new information regarding the cellular and molecular mechanisms, following CXCL11/CXCL12 and CXCR3/CXCR4/CXCR7 interactions, which modulate BrCa progression. Importantly, these studies are the first required to demonstrate the efficacy of mut-CXCL11-Ig for BrCa.