Dr. Jie Xu & Dr. Dongmei Sun's paper entitled "The Role of Prolactin Receptor in GH Signaling in Breast Cancer Cells", published in Molecular Endocrinology, has been selected as the Department of Medicine's paper of the month for January 2013.
Jie Xu obtained her MD degree and a Master's in Clinical Oncology from Wuhan University School of Medicine, China. She obtained a Ph.D. in Pathology from UAB, followed by postdoctoral fellowship and residency in Pathology also at UAB where she is currently a PGY-3 resident in Anatomic and Clinical Pathology. Dr. Jie Xu is the recipient of several awards and training grants and the first author or co-author of many publications. She has presented her research findings in several national meetings. Her major research interests are in the area of molecular endocrinology.
Dongmei Sun received her bachelor degree from the East China University of Science and Technology in Shanghai China, and her PhD in Cell Biology from the University of University of Alabama at Birmingham in 2010. She is currently a Research Associate in the Division of Endocrinology of Department of Medicine.
The focus of Dr. Stuart Frank's research is understanding mechanisms of action of growth hormone (GH), an important metabolic and growth promoting hormone. In particular, we are interested in various aspects of GH receptor (GHR) structure and signal transduction. Our studies have examined the interaction of the GHR with a critical non-receptor cytoplasmic tyrosine kinase, JAK2, which is required for initiation of GHR signaling. We have explored the downstream signaling pathways (STAT, MAP kinase, and PI-3 kinase) activated by GH and their effects on GH-induced gene expression. Further, we are interested in the cellular determinants of sensitivity to GH and modulation of GHR availability and function.
Mol Endocrinol. 2012 Nov 28. [Epub ahead of print]
The Role of Prolactin Receptor in GH Signaling in Breast Cancer Cells.
Xu J, Sun D, Jiang J, Deng L, Zhang Y, Yu H, Bahl D, Langenheim JF, Chen WY, Fuchs SY, Frank SJ.
GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHR(ext-mAb). Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells.
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