title: Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation.
abstract: Mammalian glutaredoxin 3 (Grx3) has been shown to be important for regulating cellular redox homeostasis in the cell. Our previous studies indicate that Grx3 is significantly overexpressed in various human cancers including breast cancer and demonstrate that Grx3 controls cancer cell growth and invasion by regulating reactive oxygen species (ROS) and NF-κB signaling pathways. However, it remains to be determined whether Grx3 is required for normal mammary gland development and how it contributes to epithelial cell proliferation and differentiation in vivo. In the present study, we examined Grx3 expression in different cell types within the developing mouse mammary gland (MG) and found enhanced expression ofGrx3at pregnancy and lactation stages. To assess the physiological role of Grx3 in MG, we generated the mutant mice in whichGrx3was deleted specifically in mammary epithelial cells (MECs). Although the reduction ofGrx3expression had only minimal effects on mammary ductal development in virgin mice, it did reduce alveolar density during pregnancy and lactation. The impairment of lobuloalveolar development was associated with high levels of ROS accumulation and reduced expression of milk protein genes. In addition, proliferative gene expression was significantly suppressed with proliferation defects occurring in knockout MECs during alveolar development compared with wild-type controls. Therefore, our findings suggest that Grx3 is a key regulator of ROS in vivo and is involved in pregnancy-dependent mammary gland development and secretory activation through modulating cellular ROS.
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Khanh
authors.initials: K
authors.lastname: Pham
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas.
authors.forename: Xiqian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Walter
authors.initials: W
authors.lastname: Olea
authors.affiliation: Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas.|Center for Drug Discovery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas; and.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Department of Medicine, Baylor College of Medicine, Houston, Texas.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas; and.|Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Hadsell
authors.affiliation: USDA/ARS Children Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; ncheng@bcm.edu.|Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas; and.
authors.forename: Ninghui
authors.initials: N
authors.lastname: Cheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D054477:Glutaredoxins / Q000235:genetics*; D007150:Immunohistochemistry; D007774:Lactation / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C530105:Ccnd1 protein, mouse; D054477:Glutaredoxins; D008894:Milk Proteins; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D019938:Cyclin D1
keywords: alveologenesis; breast cancer; glutaredoxin; mammary epithelial cells; mammary gland