|M.Sc Student||Martinez-Conde Antonia|
|Subject||The Effect of hSef Gain and Loss of Function on Breast|
|Department||Department of Biology||Supervisor||Professor Dina Ron|
Growth factors (GF) and pro-inflammatory cytokines (PIC) regulate a plethora of physiological processes, while deregulation of their signaling has been implicated in a variety of human diseases including cancer and inflammation. GFs and PICs induce the expression of Sef as part of a negative feedback mechanism to temper the pathway output. Sef is a tumor suppressor that inhibits various RTK signaling pathways including the PI-3K, the Ras/MAPK and p38 MAPK pathways. Recently, we found that Sef is also an inhibitor of PIC signaling where it sequesters NF-kB(p50;p65) in the cytoplasm of resting cells, and consequently prevents NF-kB nuclear entry upon cytokine stimulation. Given the involvement of RTK and NF-κB signaling in cancer promotion, Sef loss in cancer can contribute to cancer progression via multiple mechanisms. Hence, Sef expression is lost in a variety of human carcinomas including breast cancer, and its loss correlates with tumor aggressiveness. To examine whether Sef loss in breast cancer has a prognostic value, we compared survival rate of breast cancer patients to Sef expression levels in a large number of microarray data sets of breast cancer. We found that the reduction in Sef levels in Estrogen Receptor alpha positive (ER) tumors correlates with poor prognosis, although this type of tumors (ER) is generally related to a good prognosis. These data suggests that there could be a connection between Sef and estrogen signaling.
Estrogen receptor (ER) signaling includes the genomic activity, where ERs act as transcription factors, and the activation of PI3K/MAPK pathways via the non-classical membrane associated ER. RTK-activated MAPK signaling pathway has been shown to result in regulatory phosphorylation of the ER, leading to either activation or degradation of the receptor. We have hypothesized that Sef might negatively regulate ER signaling via its ability to modulate the PI-3K and MAPK pathways. In this thesis I aimed to gain insight into the molecular mechanism by which hSef affects estrogen receptor signaling pathways. I also studied the activity of Sef isoform that is differentially localized to breast and ovaries. Preliminary studies suggest that Sef is unlikely to affect the genomic estrogen response directly, and point to a possible role for the newly identified Sef isoform in breast cancer invasion.