Transgenic mice whose tumors model human breast cancer have been shown to have many molecular similarities to human disease and are immunologically intact. Similar to humans with breast cancer, mice develop low level immune responses directed against cancer associated proteins. Detection of tumor specific immunity will allow the development of assays that may be able to identify markers associated with cancer "exposure", thus, serve as potential diagnostic biomarkers. Furthermore, proteins that become immunogenic early in the malignant transformation may be ideal candidates for the development of vaccines for cancer prevention. Preliminary studies, described in this application, have demonstrated the tumor specific immunity that will arise in transgenic mice significantly mirrors the immunogenic repertoire of human patients with breast cancer and, as such, transgenic mouse models of breast cancer provide an instrument of both discovery and testing of potential immunologic targets for cancer diagnosis and preventative vaccines. We will focus our efforts on two transgenic models of breast cancer;the TgMMTV-neu and TgC3(I)-Tag mouse. The TgMMTV-neu animal demonstrates a molecular phenotype that is typical of human luminal breast cancer which accounts for nearly 2/3 of all human breast cancers. Thus, markers discovered in this animal would have broad applicability to breast cancer diagnosis and treatment. The TgC3(I)-Tag mouse has molecular similarity to a basal cell phenotype. Together these animals could potentially represent the majority of all human breast cancers.
The aims of this application are to: (1) identify immunogenic proteins associated with cancer initiation in transgenic mice developing breast cancer that may serve as candidate diagnostic and vaccine targets for human breast cancer, (2) determine whether immunogenic proteins associated with cancer initiation in transgenic mice elicit similar antibody immunity in breast cancer patients and can be used to discriminate patients with the disease from controls, and (3) determine whether a vaccine composed of immunogenic proteins associated with cancer initiation in transgenic mice can safely prevent the development of breast cancer and whether antigenic epitopes suitable for a human preventative breast cancer vaccine can be identified. Proteins expressed on mouse and human breast cancers can activate immune responses, and are molecularly similar. We plan to identify immune stimulatory breast cancer proteins in mice, and determine whether they can prevent disease or inhibit tumor growth. Then, we will see whether their human homologs can activate immune responses and potentially be used as biomarkers of breast cancer in humans.
|Mao, Jianning; Ladd, Jon; Gad, Ekram et al. (2014) Mining the pre-diagnostic antibody repertoire of TgMMTV-neu mice to identify autoantibodies useful for the early detection of human breast cancer. J Transl Med 12:121|
|Gad, Ekram; Rastetter, Lauren; Slota, Meredith et al. (2014) Natural history of tumor growth and immune modulation in common spontaneous murine mammary tumor models. Breast Cancer Res Treat 148:501-10|
|Disis, Mary L; Stanton, Sasha E (2013) Can immunity to breast cancer eliminate residual micrometastases? Clin Cancer Res 19:6398-403|
|Disis, Mary L; Gad, Ekram; Herendeen, Daniel R et al. (2013) A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res (Phila) 6:1273-82|
|Dang, Yushe; Wagner, Wolfgang M; Gad, Ekram et al. (2012) Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells. Clin Cancer Res 18:3122-31|
|O'Meara, Megan M; Disis, Mary L (2011) Therapeutic cancer vaccines and translating vaccinomics science to the global health clinic: emerging applications toward proof of concept. OMICS 15:579-88|
|Kievit, Forrest M; Florczyk, Stephen J; Leung, Matthew C et al. (2010) Chitosan-alginate 3D scaffolds as a mimic of the glioma tumor microenvironment. Biomaterials 31:5903-10|