Targeted expression of activated Rac3 in mammary epithelium leads to defective postlactational involution and benign mammary gland lesions.
Rac3, a novel member of the Rho subfamily of the small GTPases, is frequently activated in cultured breast cancer cells and has been shown to mediate its effect via the p21-activated kinase (Pak) pathway. In order to evaluate these findings in vivo, we generated transgenic mice that express human constitutively active V12Rac under the control of the mouse mammary tumor virus (MMTV) promoter, which targets the transgene expression to the mammary epithelium. V12Rac3 expression could be detected during the first pregnancy, and the transgenic mammary gland tissues displayed an elevated Pak1 phosphorylation. Although milk proteins, beta-casein and whey acidic protein were expressed and milk fat globules accumulated normally during pregnancy, 60% of transgenic mothers failed to nurse their pups. Surprisingly, although full lactational differentiation was never achieved in transgenic mice, gland involution was incomplete. For 5 days after weaning, involution was normal, but thereafter, epithelial islands characteristic of this early stage of involution persisted for months. The apoptotic index decreased after 5 days, and these glands were associated with increased p38 MAPK phosphorylation. Nine months postpartum, the transgenic mammary glands still demonstrated a large amount of persistent epithelial islands and abnormally large ducts with lymphocyte infiltration, whereas the tissues of non-transgenic controls had returned to their normal 'virgin-like' phenotype. These data show that sustained activation of Rac3 in the mammary epithelium leads to impaired mammary gland physiology and results in the formation of mammary gland lesions.
Leung
Karen
K
Developmental Biology Program, Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles Research Institute, Los Angeles, CA 90027, USA.
Nagy
Andre
A
Gonzalez-Gomez
Ignacio
I
Groffen
John
J
Heisterkamp
Nora
N
Kaartinen
Vesa
V
D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018390:Gene Targeting; D006801:Humans; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C411563:RAC3 protein, human; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C498771:Rac3 protein, mouse; D020744:rac GTP-Binding Proteins