MAPK - A Critical Intermediate in Anti-Estrogen Resistance

摘要

In the last dedade, numerous studies have indicated that polypeptide growth factors and their receptors play an important role in breast cancer and have mitogenic effects. One such family constitutes the heregulins (ERGs), EGF- like growth factors that bind directly to the erbB3 and erbB4 receptors and induce tyrosine phosphorylation of erbB2 via receptor heterodimerization. Previous studies from our laboratory, have demonstrated that HRG-beta2 induces estrogen- independent growth, estrogen receptor down-regulation, enhances cell proliferation, tumorigenicity and metastasis when stably transfected into estrogen receptor positive MCF-7 breast cancer cells. Some evidence suggests a role for the Ras-Raf-MAPK pathway in HRG signaling. HRG induces tyrosine phosphorylation of SHC and its association with GRB2-SOS complex, which in turn%can activate p21ra5. It also activates a down stream target of ras, p42/44 MAPK. The Ras-Raf-MAPK pathway is required for proliferative response to many growth factors and hormones. A cross talk has also been established between MAPK and estrogen receptor (ER), since MAPK can activate ER independent of estrogen by stimulating its phosphorylation at Ser 118. In this study, we have used a GDP-bound dominant negative mutant of ras (N17) in order to determine the involvement of Ras/-Raf-MAPK pathway in acquisition of HRG-induced estrogen- independent phenotype.