The status of the 66-kDa human
estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human
breast cancer. Recently, we cloned the
cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted
protein lacks both transcriptional activation domains of hER-alpha66 but retains its
DNA-binding domain, partial dimerization, and
ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to
estrogen signaling. We now demonstrate that hER-alpha36 inhibits the
estrogen-dependent and
estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both
estrogen- and
antiestrogen-dependent activation of the
mitogen-activated protein kinase/
extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both
estrogen-dependent and
estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated
estrogen-dependent activation of the
mitogen-activated protein kinase/
extracellular signal-regulated kinase mitogenic signaling pathway. The
estrogen and
antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast
cancers are resistant to and others are worsened by
antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct
therapy in human breast
cancers, and perhaps hER-alpha36 also may transduce
estrogen-dependent signaling in other
estrogen target tissues.