Date of Award
Doctor of Philosophy (PhD)
Chen, Wen Y
The MMTV/neu transgenic mouse line is a well-documented animal model for studying HER2/neu-related breast cancer. It has been reported that a small percentage, approximately 20%, of the virgin female MMTV/neu mice seems resistant to the development of mammary gland adenoma, despite the overexpression of the neu oncogene.
To identify the factors that are responsible for the tumor resistance in these MMTV/neu female transgenic mice, comparative genetic profiling was used to screen the alterations in gene expression in the mammary gland. A novel gene named the RAS Association domain (RalGDS/AF-6) Family 3 (Rassf3), which belongs to a family of RAS effectors and tumor suppressor genes was identified in this study. Data presented in this dissertation show: 1) that the Rassf3 gene is overexpressed in the mammary gland of the tumor-resistant MMTV/neu mice compared to their tumor-susceptible MMTV/neu transgenic littermates or age-matched non-transgenic FVB mice, and 2) that the Rassf3 gene is significantly up-regulated in neu-specific mouse mammary tumors compared to adjacent normal tissues.
To further confirm the role of the Rassf3 gene in mammary carcinogenesis, a series of in vitro and in vivo experiments were explored. The results show that overexpression of RASSF3 inhibits cell proliferation in HER2 positive human and mouse breast cancer cell lines. The inhibitory effect of RASSF3 seems to be through induction
of apoptosis. In addition, co-transfection of the Rassf3 gene with the activated H-RAS gene in SKBR3 human breast cancer cells decreased H-RAS protein level, suggesting that RASSF3 protein can indirectly interact with H-RAS protein. A novel MMTV/Rassf3-neu bi-transgenic mouse line, overexpressing both Rassf3 and neu genes in mammary glands, was also established. The mammary tumor incidence in virgin female bi-transgenic mice was delayed compared to their MMTV/neu+/- littermates. Together, these data suggest that Rassf3, a RAS effector, is a candidate gene that may influence the mammary tumor incidence in virgin female MMTV/neu transgenic mice.
Jacquemart, Isabelle, "Identification of the Rassf3 Gene as a Potential Tumor Suppressor Responsible for the Resistance to Mammary Tumor Development in MMTV/neu Transgenic Mice" (2006). All Dissertations. 26.