title: Blockade of estrogen-stimulated proliferation by a constitutively-active prolactin receptor having lower expression in invasive ductal carcinoma.
abstract: A comprehensive understanding of prolactin's (PRL's) role in breast cancer is complicated by disparate roles for alternatively-spliced PRL receptors (PRLR) and crosstalk between PRL and estrogen signaling. Among PRLRs, the short form 1b (SF1b) inhibits PRL-stimulated cell proliferation. In addition to ligand-dependent PRLRs, constitutively-active varieties, missing the S2 region of the extracellular domain (ΔS2), naturally occur. Expression analysis of the ΔS2 version of SF1b (ΔS2SF1b) showed higher expression in histologically-normal contiguous tissue versus invasive ductal carcinoma. To determine the function of ΔS2SF1b, a T47D breast cancer line with inducible expression was produced. Induction of ΔS2SF1b blocked estrogen-stimulated cell proliferation. Unlike intact SF1b, induction of ΔS2SF1b had no effect on PRL-mediated activation of Stat5a. However induction inhibited estrogen's stimulatory effects on serine-118 phosphorylation of estrogen receptor α, serine-473 phosphorylation of Akt, serine-9 phosphorylation of GSK3β, and c-myc expression. In addition, induction of ΔS2SF1b increased expression of the cell cycle-inhibiting protein, p21. Thus, increased expression of ΔS2SF1b, such as we demonstrate occurs with the selective PRLR modulator, S179D PRL, would create a physiological state in which estrogen-stimulated proliferation was inhibited, but differentiative responses to PRL were maintained.
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
authors.forename: Kuang-Tzu
authors.initials: KT
authors.lastname: Huang
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA; College of Medicine/Institute of Medical Sciences, Jishou University, Jishou, Hunan 416000, China.
authors.forename: Dunyong
authors.initials: D
authors.lastname: Tan
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
authors.forename: Kuan-Hui E
authors.initials: KE
authors.lastname: Chen
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA. Electronic address: Ameae.walker@ucr.edu.
authors.forename: Ameae M
authors.initials: AM
authors.lastname: Walker
mesh_terms: D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011981:Receptors, Prolactin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D011981:Receptors, Prolactin; D004958:Estradiol
keywords: Breast cancer; C-myc; Dominant negative prolactin receptor; Estrogen; GSK3β; Prolactin; Receptor hetero-dimerization; Stat5