Role of Constitutively Active Prolactin Receptors in the Natural History of Breast Cancer

摘要

Prolactin (PRL) has been implicated as a contributing factor in the incidence of breast cancer. Its cognate receptor (PRLR) is a single- transmembrane receptor that normally requires ligand binding to trigger intracellular signaling. Several isoforms of the human PRLR have been identified, including a long form (LF) and two short forms (SF1a and SF1b). These isoforms share identical amino acid sequences in their extracellular domains, which consist of two structurally-similar subdomains, S1 and S2, but differ in their cytoplasmic domains. Recently, we identified the existence of naturally-occurring S2-deleted (deltaS2) variants of each of these receptors in several human cell lines. These isoforms were constitutively dimerized and activated in the absence of PRL. Because of its potential anti-cancer effects, we focused most of the study on the deltaS2 SF1b isoform. Increased expression of this isoforms in stable cell lines inhibited cell proliferation and migration. When expressed in human breast cancer cells (T-47D) driven by a Tet- responsive promoter, deltaS2 SF1b inhibited both basal and estrogen-stimulated growth. This latter was in part due to decreased serine phosphorylation of estrogen receptor alpha and Akt.