The Role of Amplified Wild-Type Neu in the Etiology of Breast Cancer
Final rept. 1 Jul 2001-30 Jun 2004
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Many human breast cancers have amplified wild-type Neu Her2 protooncogenes. It is still not known from either human or rodent models if amplified wild-type Neu is involved in the etiology of breast cancer, We have begun to develop rat transgenic models. Under the first aim we will construct additional Neu transgenic rat lines. Aim 2 will endocrinologically manipulate female Neu-transgenic rats in a way that models high androgen postmenopausal women. Aim 3 will explore alternative reasons of why these female transgenics do not develop breast cancer. The role of genetic background as it relates to female breast cancer development in this model will be explored. We have produced two independent strains of Neu-transgenic rats that spontaneously develop mammary carcinomas in males. Females supplemented with androgens develop mammary carcinomas. These carcinomas activated Neu by amplification and not by mutagenesis. We have thus developed a useful model of Neu associated mammary carcinogenesis. This answers a key question of whether the amplification of wild-type Neu is only associated with tumor progression or is it also possibly involved in breast cancer etiology. These data presented is the first model to clearly demonstrate that the amplification of wild type Neu can induce mammary cancer. In addition we also show that the genetic penetrance of neu can be altered by different modifier genes on varying genetic backgrounds. This suggests that these modifiers may be good biomarker or drug targets for neu associated breast cancer.
- Anatomy and Physiology
- Medicine and Medical Research