Abstract 623: Identifying candidate antigens for a ductal carcinoma in situ vaccine that are essential to breast cancer survival across multiple subtypes

Abstract

Abstract Vaccine therapy may be ideal to destroy ductal carcinoma in situ (DCIS) and prevent recurrence. A vaccine can induce type 1 T-cells against DCIS antigens that could migrate from the circulation to invade and destroy the tumor as well as generate immunologic memory to provide long lasting protective immunity. One of the limitations to developing a DCIS vaccine is identifying antigens that target all subtypes of DCIS. DCIS has many of the same molecular abnormalities as invasive breast cancer (IBC), including overexpressed proteins that may be drivers of progression to invasive disease. Eliminating cells that are overexpressing driver proteins by vaccination may prevent progression to IBC if such proteins could be determined. In this study, we identified proteins that were overexpressed from normal breast in both DCIS and IBC across fifteen Geo and Array Express data sets. From 68 candidate proteins, we identified twelve whose expression was necessary for cancer cell survival across breast cancer subtypes. We selected overexpressed proteins necessary for cancer survival using a high throughput siRNA screen and chose candidates that increased apoptosis and decreased cell survival in HER2 positive (HER2), triple negative (TN), and hormone receptor positive HER2 negative (HR) human breast cancer cell lines with decreased expression of the target protein. For example, decreased expression of NDC80 caused decreased cell survival to 56±3% in HR, 46±3% in TN, and 77±2% in HER2 breast cancer cell lines and increased apoptosis by 1.4±0.03 fold in HR and 1.2±0.03 fold in TN breast cancer cell lines. Decreased expression of RRM2 caused decreased cell survival to 66±3% in HR and 89±2% in HER2 breast cancer cell lines and increased apoptosis by 1.6±0.08 fold in HR, 1.4±0.07 fold in TN, and 2.4±0.3 fold in HER2 breast cancer cell lines. Twelve proteins (AURKA, KIF11, NDC80, RRM2, SDC1, UBE2C, HJURP, CENPA, CENPF, HIST2H2AA3, HIST1H2BD, and TOP2A) were essential for cancer cell survival in at least 2 breast cancer subtypes. These protein targets are immunogenic in patients with DCIS. In the sera of women without breast atypia (n=36), autoantibodies to NDC80 were detected with a mean of 5.3±1.8 ng/mL while in women with fibroadenoma (n=36) autoantibodies were detected with a mean of 8.3±1.5 (p=0.05). In the sera of women without breast atypia (n=36), autoantibodies to RRM2 were detected with a mean of 0.16±0.7 ng/mL while in women with fibroadenoma (n=36) autoantibodies were detected with a mean of 7.2±2.1 (p=0.05) and in women with DCIS (n=59) autoantibodies were detected with a mean of 2.6±0.6 ng/mL (p=0.0003). These proteins represent DCIS antigens of biologic importance in tumor growth and, potentially, progression to IBC and are candidate immunogens for a vaccine to treat DCIS. Citation Format: Sasha Elizabeth Stanton, Erik Ramos, James Annis, Andrew Timms, Tessa Rue, Mary L. Disis. Identifying candidate antigens for a ductal carcinoma in situ vaccine that are essential to breast cancer survival across multiple subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 623. doi:10.1158/1538-7445.AM2017-623