When metastatic breast tumors do not respond to treatment (e.g., chemotherapy, endocrine therapy, and targeted therapies), ultimately the patient dies. Understanding the molecular events that cause metastatic recurrence after treatment and identifying effective second and third line therapies to treat recurrent tumors will significantly improve patient outcomes. We previously identified the transcription factor ZNF217 (human)/Zfp217 (mouse) as a prognostic marker of poor outcome in breast cancer patients. ZNF217 is overexpressed in breast and other cancers, and this overexpression promotes reduced survival, increased metastasis, and reduced response to therapy in patients and in our animal models. We found that Zfp217 overexpression promotes an increase in self-renewal capacity, invasion, and metastasis, as well as expansion of a progenitor cell population during both normal mammary development and breast cancer progression.
We hypothesized that Zfp217 overexpression promotes resistance to therapies by expanding a progenitor cell population that can metastasize and remain resistant to chemotherapy. To determine experimentally if Zfp217 overexpression in vivo caused chemotherapy resistance, we used mouse orthotopic transplants of mouse breast cancer cells ± Zfp217 in syngeneic hosts. After treatment with combination chemotherapies (i.e., microtubule inhibitor epothilone B, adriamycin, and cyclophosphamide (EAC)), the mice overexpressing Znf217 developed chemoresistance with increased tumor volume and decreased percent survival compared to control mice. Treated mice that overexpressed Znf217 in their tumors had increased tumor burden compared to control animals. These data suggested that mice overexpressing Znf217 developed resistance to the EAC chemotherapy. Interestingly, the chemoresistant tumors that overexpress Zfp217 had increased numbers of progenitor cells that expressed markers of both luminal and myoepithelial cells (K8+K14+). In addition, chemotherapy treatment reduced but did not eliminate lung metastases compared to controls.
Because ZNF217 is expressed at the highest levels in breast cancer patients with the worst prognosis, we aimed to identify treatments that kill chemoresistant cancer cells that overexpress ZNF217. To overcome breast cancer chemoresistance caused by ZNF217 overexpression, we identified triciribine, a nucleoside analog and AKT inhibitor, as a drug that kills cells that overexpress ZNF217. Currently triciribine is in a Phase I-II clinical trial using triciribine monophosphate in combination with the microtubule inhibitor paclitaxel in patients with breast and other cancers. The Phase I trial is completed, and the Phase II trial is recruiting patients. To model the Phase II clinical trial and to determine if Zfp217 overexpression is predictive of response to triciribine in breast cancer, we tested the efficacy of triciribine with paclitaxel and tested the order of treatment with paclitaxel and triciribine combination therapy by in vivo transplantation of mammary cancer cells ±Zfp217 overexpression. We found that the treatment order significantly impacted triciribine's therapeutic efficacy. This study directly influenced the design of the Phase II clinical trials with triciribine and paclitaxel in metastatic breast cancer patients. In addition, our animal models of chemoresistance after Zfp217 overexpression will be used to study the mechanisms of therapeutic resistance by the expansion of a progenitor cell population.
Citation Format: Christopher Suarez, Joseph Sparano, Sunil S. Badve, Laurie E. Littlepage. Overcoming resistance to chemotherapy using ZNF217 as a predictive marker and therapeutic target of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B37.