Abstract P2-07-05: Age-Related Changes in ERK5 Signaling and Crosstalk with ERK1/2 and PI3K in Breast Cancer

Increasing age is a main risk factor for breast cancer. By the year 2040, the number of Americans age 65 or older is expected to more than double to nearly 80 million. Therefore, the need to define the underlying mechanisms involved in breast tumor proliferation with aging is crucial. Previous studies have shown that mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5) expression and activity increase with age in breast cancer patients. Furthermore, patients with increased levels of ERK5 have been found to have a poorer prognosis than those with lower levels. The MAPK and phosphatidylinositol 3-kinase (PI3K) signaling cascades play essential roles in several cellular processes including proliferation, survival, and apoptosis. In breast cancer cells, crosstalk between the MAPK extracellular signal-regulated kinase 1/2 (ERK1/2) and PI3K pathways has been found to play an important role in cellular proliferation and chemoresistance. Therefore, our hypothesis is that as ERK5 activity increases, ERK1/2 and PI3K activities decrease, and vice versa, to promote the proliferation of breast cancer cells with aging. The human breast cancer BT-474 and MDA-MB-231 cell lines and the murine cancer, MMC, cell line were utilized for our in vitro studies of ERK and Akt expression and activation. To mimic aging in vitro, cells were maintained in culture out to 36 passages with intermittent lysates collected at every third passage. In the BT-474 (ER+/PR+/HER2 high ) cell line, increased ERK5 activity was observed in the middle passages; ERK1/2 activation and expression remained unchanged between the different passages collected. Conversely, no ERK5 activity was observed in the MDA-MB-231 (ER-/PR-/HER2 low ) cell line, while ERK1/2 activity and expression again remained unchanged throughout the different passages. These observations suggest the potential of age-related and hormonal influences on ERK5 activation and require further investigation. To confirm our findings in vivo, the MMTV -neu transgenic mouse model was employed. These female mice spontaneously develop mammary tumors thereby mimicking the development of human breast cancers. Tumors were extracted from young (3 mo), middle-aged (9 mo), and old (15 mo) mice. Data from our in vivo studies suggest that ERK5 activity increases at middle-age, confirming our observations in vitro. Interestingly, ERK1/2 activation decreased in the middle-age group. Such findings suggest the presence of a compensatory mechanism between the MAPKs. Ongoing studies are examining the crosstalk between these pathways and the PI3K pathway. Specific inhibitors of the pathways and small interfering RNA (siRNA) will be used to selectively decrease ERK1/2, ERK5 and PI3K signaling. Cell proliferation will then be assessed to evaluate the relative roles of these kinases. The data obtained from these studies may lead to the identification of ERK5 as a therapeutic target in middle-aged and elderly patients thereby providing more individualized therapies that may lead to decreased breast cancer incidence and mortality. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-07-05.