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: Kuang-Tzu Huang, Dunyong Tan, Kuan-Hui E Chen, Ameae M Walker
• Journal: Cancer letters (Cancer Lett) Vol. 358 Issue 2 Pg. 152-160 (Mar 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25527452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Estrogens
• Receptors, Prolactin
• Estradiol

Topics

• Carcinoma, Ductal, Breast (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Estradiol (metabolism, pharmacology)
• Estrogens (metabolism, pharmacology)
• Female
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Neoplasm Invasiveness
• Protein Interaction Domains and Motifs
• Protein Multimerization
• Receptors, Prolactin (chemistry, genetics, metabolism)