Abstract P5-01-09: Early tumor antigens discovered in TgMMTV-neu mice may provide targets for early breast cancer diagnosis and prevention

Abstract

Abstract Breast cancer is immunogenic and breast tumor proteins stimulate both an antibody and a T cell immune response. Identification of cancer related proteins that become immunogenic prior to the clinical development of cancer may allow the use of humoral immunity to identify those “exposed” to the cancer phenotype. Alternatively, these proteins that become aberrant enough to trigger such early immune recognition may be ideal targets for a vaccine aimed at preventing the development of breast cancer. We used the TgMMTV-neu mouse model to discover immunogenic proteins i.e. proteins expressed in pre-invasive breast cancer. The mammary tumors in these mice are genotypically similar to human luminal breast cancer and can be evaluated longitudinally, allowing for collection of pre-diagnostic sera prior to tumor development to use for antigen discovery. We identified 6 antigens that were present in mice prior to the development of mammary cancer (Pdhx, Otud6b, Stk39, Zpf238, Lgals8, and Vps35). These proteins were associated with inflammation, autoimmunity, and cellular homeostasis. In mouse validation cohorts, detecting IgM and IgG antibody responses against a panel of three “pre-diagnostic” tumor antigens discriminated pre-diagnostic sera from non-transgenic control sera with an AUC of 0.924. We next evaluated samples obtained from the Women's Health Initiative Study and demonstrated women with autoantibodies to the human homologues of these proteins. IgM and IgG autoantibodies to the “pre-diagnostic” antigen panel could discriminate the samples of women who eventually developed breast cancer from matched controls. The discriminatory potential of the pre-diagnostic autoantibodies was enhanced if samples were collected more than 5 months prior to diagnosis (AUC 0.68; CI 0.565-0.787). We questioned whether these antigens, which could predict women who would eventually develop breast cancer, could mediate anti-tumor immunity. When TgMMTV-neu mice (n = 5/group) were vaccinated with the individual antigens, vaccination with Pdhx inhibited tumor growth by 62.1%, Otud6B inhibited tumor growth by 23.5%, and Stk39 inhibited tumor growth by 50.3% as compared to empty vector vaccinated control at 27 weeks (p<0.001 for each of the individual antigens as compared to empty vector). Spontaneous tumorigenesis was inhibited in TgMMTV-neu mice (n = 20 mice/group) vaccinated with a panel of three of the “pre-diagnostic” antigens (Pdhx, Otud6b, and Stk39) inhibited tumor growth by 27.3% by 37 weeks as compared to vector vaccinated mice (p<0.05). These data suggest that the same pre-invasive breast tumor proteins are found in mice and women and vaccines against these pre-invasive breast cancer proteins inhibit tumorigenesis in mice, future studies will address if these antigens elicit T-cell responses in patients with high risk breast lesions. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-01-09.