Prolactin receptor attenuation induces zinc pool redistribution through ZnT2 and decreases invasion in MDA-MB-453 breast cancer cells

• Published in: Experimental cell research Vol. 321; no. 2; pp. 190 - 200
• Main Authors: Bostanci, Zeynep, Alam, Samina, Soybel, David I., Kelleher, Shannon L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2014; Elsevier BV
• Subjects: 60 APPLIED LIFE SCIENCES; APOPTOSIS; Biological Transport - drug effects; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cation Transport Proteins - physiology; Cell adhesion & migration; CELL DIFFERENTIATION; CELL PROLIFERATION; ESTROGENS; Female; Hormone Antagonists - pharmacology; Humans; LTH; LYSOSOMES; MAMMARY GLANDS; METABOLISM; MITOCHONDRIA; Mitochondria - drug effects; Mitochondria - metabolism; MMP-2; Neoplasm Invasiveness; NEOPLASMS; Oxidation-Reduction - drug effects; PRL-R; Protein expression; RECEPTORS; Receptors, Prolactin - antagonists & inhibitors; Receptors, Prolactin - genetics; RNA, Small Interfering - genetics; Signal transduction; Tissue Distribution - drug effects; Tumor Cells, Cultured; Zinc - metabolism; ZnT2; ZnT2; Lysosomes; PRL-R; Mitochondria; Breast cancer; MMP-2
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2013.12.005

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. •PRL-R attenuation increased ZnT2 expression.•PRL-R attenuation increased lysosomal and mitochondrial Zn accumulation.•PRL-R attenuation decreased MMP-2 and invasion.•PRL-R antagonists may modulate lysosomal and mitochondrial Zn pools.