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Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor

Shuyuan Yeh^1,2, Yueh-Chiang Hu^1,2, Peng-Hui Wang^1,2,3, Chao Xie^1,2, Qingquan Xu^1,2, Meng-Yin Tsai^1,2,5, Zhihong Dong^1,2, Ruey-Sheng Wang^1,2,4, Ting-Hein Lee^1,2 and Chawnshang Chang^1,2

¹ Department of Pathology, George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, NY 14627
² Department of Urology, George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, NY 14627
³ Department of Obstetrics and Gynecology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan
⁴ Department of Obstetrics and Gynecology, Taipei Medical University Hospital,Taipei 105, Taiwan
⁵ Reproductive Medicine Institute, Chung Gong University, Kaohsiung 833, Taiwan

Address correspondence to Chawnshang Chang, George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, NY 14642. Phone: (585) 275-9994; Fax: (585) 756-4133; email: chang{at}urmc.rochester.edu

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.

Key Words: androgen receptor • knockout mice • mammary gland • breast cancer • MAPK

Abbreviations used in this paper: AR, androgen receptor; BrdU, bromodeoxyuridine; CDS, charcoal dextran–stripped; DBD, DNA-binding domain; dprm, deletion of the proline-rich motif; E2, 17ß-estradiol; Efp, estrogen-responsive finger protein; EGF, epidermal growth factor; ER, estrogen receptor; GFP, green fluorescent protein; HGF, hepatocyte growth factor; HI, heat-inactivated; HRG-, heregulin-; IGF-I, insulin-like growth factor I; LBD, ligand-binding domain; Luc, luciferase; MAPK, mitogen-activated protein kinase; np, natural promoter–driven; P, progesterone; PR, P receptor; siRNA, small interfering RNA; TBS, Tris-buffered saline; TEB, terminal end bud; UTR, untranslated region.

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