Studies on proto-oncogene function: The roles of c-MYC and Akt1 in mammary development and tumorigenesis

Genetic and epigenetic alterations of c-MYC and AKT have been identified in human tumors, including those of the breast. To better understand the roles of c-MYC and Akt1 in the mammary gland tumorigenesis, we have characterized animal models in which c-MYC and Akt1 are conditionally expressed in the mammary glands of transgenic mice. From these studies, we have determined that the vast majority of c-MYC-induced mammary adenocarcinomas progress to a state that is independent of c-MYC transgene expression. These results highlight the importance of identifying oncogenic pathways that frequently cooperate with c-MYC during mammary tumorigenesis. Towards this goal, we have found that fifty percent of c-MYC-induced mammary tumors harbor spontaneous activating point mutations in ras genes and that an additional subset of tumors exhibit increased Akt activity. Consistent with these results, coexpression of c-MYC and Akt1 dramatically reduced tumor latency and increased tumor multiplicity compared to expression of either oncogene alone. To investigate potential mechanisms for the synergy between c-MYC and Akt1, we have evaluated the effects of Akt1 expression in the mammary gland and have found that Akt1 expression induced high levels of mammary epithelial cell proliferation. Furthermore, continued Akt1 expression resulted in the development of invasive mammary adenocarcinomas. These results represent the first demonstration of Akt1's ability to promote mammary tumorigenesis in vivo. In addition to Akt1's effects on mammary epithelial cell proliferation and transformation, we have also shown that Akt1 can induce secretory differentiation in ductal mammary epithelial cells of virgin mice. Interestingly, endogenous Akt1 expression in the mammary gland peaks during late pregnancy and lactation, suggesting that Akt1 may normally be required for mammary gland development. Using mice with targeted deletions in Akt1 and/or Akt2, we have characterized a non-redundant role for Akt1 during secretory activation of the mammary gland. Thus, we have found that Akt1 normally functions in the development of the mammary gland and when dysregulated promotes its transformation. By increasing our understanding of the effects of Akt1 and c-MYC in the mammary gland, we hope these studies will aid the development of effective therapeutic strategies for the prevention and treatment of breast cancer.