Breast cancer vaccines composed of
antigens identified by serological analysis of
cDNA expression libraries (SEREX) induce
antigen specific immune responses in patients but have had disappointing clinical benefits. While many attempts to modify the adjuvants and
vaccine method have been tried, one issue not addressed was whether the SEREX
tumor-associated
antigens identified from late stages of disease were ideal targets. We questioned in the transgenic TgMMTV-neu mouse model whether the
antigen repertoire is distinct between early and late stage
breast cancer and whether the
antigens identified via SEREX from transgenic mice with early or late stage
tumors would elicit differential anti-
tumor effects to address this question. Three early stage
antigens, Pdhx, Stk39, and Otud6B, were identified from a SEREX screen of mice prior to development of palpable lesions. Formulated into a
vaccine, each early
antigen inhibited
tumor growth (p < 0.0001). The
antigens identified from mice with late stage
tumors (Swap70, Gsn, and Arhgef2) were unable to inhibit
tumor growth when used as
vaccines (for example Gsn p = 0.26). Each of the three early stage
antigens were essential for
tumor survival in syngeneic mouse
tumor cells and in human
breast cancer cell lines across
breast cancer subtypes. Silencing
protein expression of the early
antigens increased apoptosis (p < 0.0001 for all
antigens in mouse and p < 0.05 for all
antigens in human
triple negative breast cancer) and decreased survival (p < 0.0001 for all
antigens in mouse and human triple negative and HER2 positive
breast cancer). Overexpression of the early stage
antigens in women with
breast cancer predicted worse prognosis (p = 0.03) while overexpression of late stage
antigens did not impact prognosis (p = 0.09). These data suggest that
antigens expressed earlier in
breast tumor development and functionally relevant to
breast tumor growth may be more effective targets for therapeutic
breast cancer vaccines than
antigens identified in later disease.