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 of Grx3 at pregnancy and lactation stages. To assess the physiological role of Grx3 in MG, we generated the mutant mice in which Grx3 was deleted specifically in mammary epithelial cells (MECs). Although the reduction of Grx3 expression 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: Khanh Pham, Jie Dong, Xiqian Jiang, Ying Qu, Han Yu, Yisheng Yang, Walter Olea, Juan C Marini, Lawrence Chan, Jin Wang, Xander H T Wehrens, Xiaojiang Cui, Yi Li, Darryl L Hadsell, Ninghui Cheng
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 312 Issue 3 Pg. E136-E149 (03 01 2017) ISSN: 1522-1555 [Electronic] United States
• PMID: 27894063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ccnd1 protein, mouse
• Glutaredoxins
• Milk Proteins
• NF-kappa B
• RANK Ligand
• RNA, Messenger
• Reactive Oxygen Species
• Receptor Activator of Nuclear Factor-kappa B
• Receptors, Progesterone
• Tnfrsf11a protein, mouse
• Tnfsf11 protein, mouse
• Cyclin D1

Topics

• Animals
• Blotting, Western
• Cell Proliferation (genetics)
• Cyclin D1 (genetics)
• Epithelial Cells (metabolism)
• Female
• Gene Expression Regulation, Developmental
• Glutaredoxins (genetics)
• Immunohistochemistry
• Lactation (genetics)
• Mammary Glands, Animal (growth & development, metabolism)
• Mice
• Mice, Knockout
• Milk Proteins (genetics)
• NF-kappa B (metabolism)
• Pregnancy
• Pregnancy, Animal
• RANK Ligand (metabolism)
• RNA, Messenger (metabolism)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptor Activator of Nuclear Factor-kappa B (metabolism)
• Receptors, Progesterone (metabolism)
• Signal Transduction