ErbB-2 (Her2/neu) is an oncogene encoding a 185 kDA (p185neu) tyrosine kinase receptor involved in cell differentiation, adhesion and motility. Mice made transgenic for the unactivated form of rat neu/erbB-2 [FVB/N-Tg(MMTVneu)202Mul/J] display a high incidence and aggressive progression of mammary carcinogenesis. In this model, focal mammary tumors are first apparent at 4 months of age in >50% of the mice, with a median incidence of 205 days. The tumors arise as hyperplastic/dysplastic foci in mammary glands; and ~70% of tumor-bearing mice >8 months of age develop lung metastases. Also, there is substantial evidence that cytokine gene therapy with IL12 results in regression of tumors in these mice. Therefore, this transgenic mouse is a highly useful model for studying the effects of stress on incidence and development of breast cancer and anti-tumor immunity to those tumors. We propose to use chronic stress models in combination with this spontaneous tumor model to document the effects of stress on tumor development, to evaluate the mechanisms resulting in enhanced tumor development, and to assess the negative effects of stress on tumor immunity. In addition, we will examine the effects of stress on the efficacy of tumor immunotherapy with IL12.
Our specific aims i nclude:
Aim 1. Determine the effects of chronic stressors on mammary tumor development and lung metastases in Erbb-2 transgenic [FVB/N- Tg(Mmtvneu)202Mul/J] mice.
Aim 2. Determine the effects of chronic stress on anti-tumor immunity in Erbb-2 transgenic [FVB/N-Tg(Mmtvneu)202Mul/J] mice. This project deals with the evaluation of the effects of stress on the progression, and possibly initiation, of breast cancer in a transgenic mouse model. In this model, breast tumors spontaneously develop in about half the mice; and we will determine whether stress increases to rapidity of tumor development and whether it increases the number of mice that develop tumors. We will also examine whether stress affects the ability of the mice to mediate anti- tumor immune responses to breast cancer. This may provide an important advance in the experimental approaches available to monitor the effects of stress on cancer. ? ? ?
