Location: Children's Nutrition Research CenterTitle: Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation
|PHAM, KHANH - Children'S Nutrition Research Center (CNRC)|
|DONG, JIE - Baylor College Of Medicine|
|JIANG, XIQIAN - Baylor College Of Medicine|
|YING, QU - Cedars-Sinai Medical Center|
|YU, HAN - Children'S Nutrition Research Center (CNRC)|
|YANG, YISHENG - Case Western Reserve University (CWRU)|
|OLEA, WALTER - Baylor College Of Medicine|
|MARINI, JUAN - Children'S Nutrition Research Center (CNRC)|
|CHAN, LAWERENCE - Baylor College Of Medicine|
|WANG, JIN - Baylor College Of Medicine|
|WEHRENS, XANDER - Children'S Nutrition Research Center (CNRC)|
|CUI, XIAOJIANG - Cedars-Sinai Medical Center|
|LI, YI - Baylor College Of Medicine|
|HADSELL, DARRYL - Children'S Nutrition Research Center (CNRC)|
|CHENG, NINGHUI - Children'S Nutrition Research Center (CNRC)|
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2016
Publication Date: 11/15/2016
Citation: Pham, K., Dong, J., Jiang, X., Ying, Q., Yu, H., Yang, Y., Olea, W., Marini, J.C., Chan, L., Wang, J., Wehrens, X.H., Cui, X., Li, Y., Hadsell, D.L., Cheng, N. 2016. Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation. American Journal of Physiology - Endocrinology and Metabolism. doi:10.1152/ajpendo.00150.2016.
Interpretive Summary: Our previous report indicates that the antioxidant protein, glutaredoxin 3 (Grx3), is important for human breast cancer development. However, the detailed knowledge about the function of Grx3 in the mammary gland development is still not fully understood. Scientists from the Children Nutrition Research Center (CNRC) in Houston, TX in collaboration with scientists from other institutions studied the transgenic mouse with deletion of Grx3 gene in mammary epithelial cells and found that Grx3 is crucial for mammary epithelial cell growth and milk production through protecting against cells death caused by oxygen free radical attack. These findings provide the molecular basis for enhancing antioxidant systems in the mammary gland to improve milk production.
Technical 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 ROS and NF-'B 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 to 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.