Mechanism of RhoB/FTI Action in Breast Cancer

摘要

Progress was made this period on the important question of how FTI efficacy is achieved in breast cancer. Clinical trials have revealed that breast cancers respond to FTI but only in a minority of cases. What factors dictate FTI efficacy. In this period, we advanced our studies of the role of cyclin B1, a key regulator of mitosis, as a critical target for RhoB suppression in FTI-induced apoptosis. Evidence that cyclin B1 downregulation was critical for FTI-induced tumor suppression was obtained. Mechanistic studies revealed that at early times RhoB suppressed the transcription and the nuclear accumulation of cyclin B1 that occurs in cells destined to undergo FTI- induced cell death. In a second line of work, we discovered that Rho and Myc interact genetically in breast tumor formation. Specifically, we found that loss of RhoB accelerated breast tumor formation in MMTV-c-myc mice. Preliminary studies suggest that this effect may be based increased stability of the c-Myc protein, prompting the hypothesis that RhoB regulates the turnover of c-Myc in cancer cells. Our work furthers the notion that cyclin B1 is a critical proapoptotic target of RhoB and it reveals suggestive interactions between RhoB and Myc in breast cancer formation.