Abstract B94: The roles of ERK1/2 and ERK5 in age-related breast cancer proliferation

Abstract

Abstract The purpose of the current study is to examine the relative roles of the extracellular signal-regulated kinases 1, 2, and 5 (ERK1/2 and ERK5) and novel benzimidazole inhibitor compounds in cellular proliferation in breast tumors with aging. Breast cancer risk progressively increases with age, in part due to an accumulation of genetic mutations that occur during cellular division and/or exposure to environmental toxins. It has been estimated that over the next thirty years the number of Americans older than 65 years of age will double. With this increase in the aged population, the incidence of breast cancer will rise; therefore, it is important to examine the underlying mechanisms involved in breast tumor proliferation with aging. It has been well established that activation of the mitogen-activated protein kinase (MAPK) ERK1/2 leads to increased cellular proliferation and differentiation in cancer cells. Many of these studies rely on pharmacological inhibitors that were thought to be specific for the ERK1/2 pathways. Interestingly, recent studies demonstrate that these inhibitors also block the activation of a novel MAPK, ERK5. Indeed, an increase in ERK5 activity has been observed in mammary tumors in aged patients. However, the roles of ERK1/2 and ERK5 in breast cancer cell proliferation with aging have not been fully explored. In our studies, the transgenic MMTV-neu mouse model was utilized to examine ERK1/2 and ERK5 activity with age. MMTV-neu mice develop spontaneous mammary tumors which make them an appropriate model for the studies of human breast cancer. Tumors were extracted from young (3 mo), middle (9 mo), and old (15 mo) mice. Higher levels of ERK5 expression and activity were observed in middle- and old-aged animals as compared to their younger counterpart. Similarly, ERK1/2 expression and activation were increased with age. To further study the role of the ERK pathways on cell proliferation with aging, the BT-474 human breast cancer cell line and the MMTV-neu cell line (MMC) were utilized. Cell lysates were collected at passages 2, 12, 24 and 36 to mimic aging. At early passages ERK5 was constitutively active under basal conditions. At later passages, an age-dependent increase in ERK5 was observed. Breast cancer cell proliferation may be regulated by ERK5 exclusively or in conjunction with ERK1/2. We next investigated how novel benzimidazole compounds can act as specific inhibitors of ERK5 signaling in MMC and BT-474 cells. Overall, these studies will provide novel information about the cellular mechanisms involved in cancer cell proliferation and progression with aging. A better understanding of the ERK1/2 and ERK5 pathways in age-related mammary cell proliferation may lead to the development of preventative therapeutics or treatment possessing enhanced specificity for aging patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B94.