Identifying pre-diagnostic breast cancer antigens in transgenic mouse mammary tumor models for preventative vaccine development.

Sasha E. Stanton, Ekram Gadd, Lauren Rastetter, James Annis, Jianning Mao, John Ladd, Samir Hanash, Mary L. Disis
Description / Abstract: 

Preventative vaccine therapy may benefit women at high risk for breast cancer but currently it is impossible to identify women who
will develop breast cancer prior to tumor development to identify initiating cancer antigens. Immunocompetent transgenic mouse
mammary tumor models that are genetically similar to human breast cancer subtypes may identify pre-invasive antigens because
mice can be followed longitudinally. Comparing tumor growth characteristics in two mouse models (TgMMTV-neu is genetically
similar to luminal B breast cancer and C3(1)tag is genetically similar to triple negative breast cancer) demonstrated that, similar to
triple negative breast cancer, C3(1)Tag mice develop tumors earlier and tumors grow more rapidly than TgMMTV-neu tumors.
Furthermore, C3(1)Tag tumors have increased CD8+/CD4+ ratio (p<0.05) similar to human triple negative tumors. Using these two
mouse models, we identified putative pre-invasive breast cancer antigens present prior to tumor development by serologic analysis
of recombinant cDNA expression libraries and serological analysis of chip-arrayed proteins. We identified 65 pre-invasive antigens
that were present in mice that would develop cancer but not parental control mice. The goal of this study was to identify which of
the 65 antigens were required for human breast cancer survival with the goal to develop a preventative multi-antigen polyepitope
breast cancer vaccine.
We chose the pre-invasive antigens necessary for human breast cancer tumor cell survival using a high throughput siRNA screen
evaluating for increased apoptosis and decreased cell survival in either HER2 positive or triple negative human breast cancer cell
lines with decreased expression of the target protein. Five of the antigens were essential for human breast cancer cell survival:
VPS35, SERBP1, ARPC2, PDIA6, and KRT8. All of these genes have roles in human cancer progression, and KRT8, SERBP1,
and PDIA6 have identified roles in breast cancer pathogenesis. After designing human MHC class II peptides for each of these
targets that cover at least 25% of the protein, we evaluated implanted tumor inhibition in the mouse models. Vaccination VPS35
peptides inhibited tumor growth by 47% (p<0.0001), vaccination with ARPC2 peptides inhibited tumor growth by 54% (p<0.0001),
and vaccination with SERBP1 peptides inhibited tumor growth by 61% (p<0.0001) in the TgMMTV-neu mice. In C3(1)Tag mice,
vaccination with VPS35 peptides inhibited tumor growth by 39% (p<0.0001) and vaccination with SERBP1 peptides inhibited tumor
growth by 59% (p<0.0001) but vaccination with ARPC2 peptides did not inhibit tumor growth. These studies have demonstrated
that mouse models can be used to identify pre-invasive breast cancer antigens. Further studies will evaluate the use of vaccines
containing epitopes from several of the antigens to prevent spontaneous tumors in these mouse models.

Other ID: 
Control/Tracking Number: 15-A-1370-AACR