Abstract 5774: Identification of novel targeted therapies for human triple-negative breast cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 8_Supplement; p. 5774
• Main Authors: Tomlinson, Christine C., Bennett, Christina N., Hollinghead, Melinda, Green, Jeffrey E.
• Format: Journal Article
• Language: English
• Published: 15-04-2010
• DOI: 10.1158/1538-7445.AM10-5774
• EISSN: 1538-7445
• ISSN: 0008-5472

Triple Negative (TN) breast cancers are characterized by the lack of estrogen receptor, progesterone receptor, and Her2 in the tumors. Currently, unlike breast cancers that are hormone responsive or Her2+, there are no targeted therapies for this subtype of breast cancer. Additionally, TN breast cancer is frequently diagnosed in younger women, often prior to the age of routine mammography with young African-American women having a disproportionately higher incidence and mortality from TN breast cancers than Caucasians. Despite advances in the treatment of breast cancer, molecular characteristics of this subtype remain poorly understood and improved therapies are critically needed.
Gene expression profiling has identified genetically engineered mouse (GEM) models that share important correlations with human breast tumor subtypes. In particular, the C3(1)/TAg GEM model appears to best represent basal-like/triple negative human breast cancers in several ways. The C3(1)TAg GEM model develops primary and metastatic mammary tumors following a progressive course characteristic of human breast tumor development, loss of p53 and Rb functions via SV40 T-antigen expression and amplifications of syntenic regions (hu. Chr. 12p12; mus. Chr. 6, a region containing K-RAS.) We have previously identified a critical proliferation/DNA repair/cell cycle gene signature (TAg signature), in primary mammary tumors from SV40 TAg mice that is also characteristic of human basal-like breast cancers. The TAg signature was also found to be highly predictive of human breast cancer prognosis.
By targeting the up-regulated genes identified in the TAg signature, we have identified novel targets for the treatment of TN breast cancer. We have also performed synthetic lethality studies in which gene knockdown has been combined with common chemotherapy agents (cisplatin and paclitaxel) and agents currently in clinical trials (gemcitabine, Chk1 and Notch signaling inhibitors) to identify novel combination therapies. Several combinations are being tested in in vivo tumor transplant and human xenograft experiments.
These studies have shown that the TAg signature can be used for the identification of new targets through siRNA screens of up-regulated genes in the signature and help determine new targets for preclinical testing of candidate drugs in novel combinations for treatment of TN breast cancer. The results of these studies may be translated into potentially effective therapies for women with aggressive forms of TN breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5774.