Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor.
Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR-/-) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR-/- mammary glands involves the defects of insulin-like growth factor I-insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor-mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR-/- MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.
Yeh
Shuyuan
S
Department of Pathology, University of Rochester, Rochester, NY 14642, USA.
Hu
Yueh-Chiang
YC
Wang
Peng-Hui
PH
Xie
Chao
C
Xu
Qingquan
Q
Tsai
Meng-Yin
MY
Dong
Zhihong
Z
Wang
Ruey-Sheng
RS
Lee
Ting-Hein
TH
Chang
Chawnshang
C
D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000502:physiology; D011944:Receptors, Androgen / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis; D014158:Transcription, Genetic
D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D004247:DNA; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases