title: Prolactin receptor attenuation induces zinc pool redistribution through ZnT2 and decreases invasion in MDA-MB-453 breast cancer cells.
abstract: Prolactin receptor (PRL-R) activation regulates cell differentiation, proliferation, cell survival and motility of breast cells. Prolactin (PRL) and PRL-R over-expression are strongly implicated in breast cancer, particularly contributing to tumor growth and invasion in the more aggressive estrogen-receptor negative (ER-) disease. PRL-R antagonists have been suggested as potential therapeutic agents; however, mechanisms through which PRL-R antagonists exert their actions are not well-understood. Zinc (Zn) is a regulatory factor for over 10% of the proteome, regulating critical cell processes such as proliferation, cell signaling, transcription, apoptosis and autophagy. PRL-R signaling regulates Zn metabolism in breast cells. Herein we determined effects of PRL-R attenuation on cellular Zn metabolism and cell function in a model of ER-, PRL-R over-expressing breast cancer cells (MDA-MB-453). PRL-R attenuation post-transcriptionally increased ZnT2 abundance and redistributed intracellular Zn pools into lysosomes and mitochondria. ZnT2-mediated lysosomal Zn sequestration was associated with reduced matrix metalloproteinase 2 (MMP-2) activity and decreased invasion. ZnT2-mediated Zn accumulation in mitochondria was associated with increased mitochondrial oxidation. Our results suggest that PRL-R antagonism in PRL-R over-expressing breast cancer cells may reduce invasion through the redistribution of intracellular Zn pools critical for cellular function.
authors: The Pennsylvania State University, Department of Nutritional Sciences, 209 Chandlee Lab, University Park, PA 16802, United States; The Pennsylvania State University Milton S. Hershey Medical Center, Department of Surgery, 500 University Dr., Hershey, PA 17033, United States. Electronic address: zbostanci@hmc.psu.edu.
authors: Zeynep
authors: Z
authors: Bostanci
authors: The Pennsylvania State University, Department of Nutritional Sciences, 209 Chandlee Lab, University Park, PA 16802, United States; The Pennsylvania State University Milton S. Hershey Medical Center, Department of Surgery, 500 University Dr., Hershey, PA 17033, United States. Electronic address: sra116@psu.edu.
authors: Samina
authors: S
authors: Alam
authors: The Pennsylvania State University, Department of Nutritional Sciences, 209 Chandlee Lab, University Park, PA 16802, United States; The Pennsylvania State University Milton S. Hershey Medical Center, Department of Surgery, 500 University Dr., Hershey, PA 17033, United States; The Pennsylvania State University College of Medicine, Department of Cell and Molecular Physiology, 500 University Dr., Hershey, PA 17033, United States. Electronic address: dsoybel@hmc.psu.edu.
authors: David I
authors: DI
authors: Soybel
authors: The Pennsylvania State University, Department of Nutritional Sciences, 209 Chandlee Lab, University Park, PA 16802, United States; The Pennsylvania State University Milton S. Hershey Medical Center, Department of Surgery, 500 University Dr., Hershey, PA 17033, United States; The Pennsylvania State University College of Medicine, Department of Cell and Molecular Physiology, 500 University Dr., Hershey, PA 17033, United States. Electronic address: slk39@psu.edu.
authors: Shannon L
authors: SL
authors: Kelleher
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000502:physiology*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010084:Oxidation-Reduction / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000235:genetics; D014018:Tissue Distribution / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D006727:Hormone Antagonists; D034741:RNA, Small Interfering; D011981:Receptors, Prolactin; C486299:SLC30A2 protein, human; D015032:Zinc
keywords: Breast cancer; Lysosomes; MMP-2; Mitochondria; PRL-R; ZnT2