Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells.
Four and a half LIM domain protein 2 (FHL2) has been implicated in development and progression of various types of cancers. However, little is known about the biological function of FHL2 in breast cancer. Here, we report that FHL2 physically and functionally interacts with estrogen receptors (ERα and ERβ), important regulators of breast cancer development and progression. The N-terminal half LIM domain or a single LIM domain of FHL2 was sufficient for its interaction with ERα and ERβ. Overexpression of FHL2 reduced ER transcriptional activity in breast cancer cells, whereas reduction of endogenous FHL2 with FHL2 small interfering RNA enhanced ER transactivation. Moreover, FHL2 cooperates with Smad4, a previously known corepressor for ERα, to inhibit ERα transcriptional activity as well as expression of the estrogen-responsive gene cathepsin D. The synergistic inhibition of ERα transcriptional activity by FHL2 and Smad4 may be due to enhanced interaction of Smad4 with ERα by FHL2, because FHL2(1-156), the FHL2 deletion mutant, which showed no synergistic effect, failed to increase such interaction. These data suggested the cooperative regulation of estrogen signaling by FHL2 and Smad4 in breast cancer cells, and might provide a new regulation mechanism underlying breast cancer development and progression.
Xiong
Zhihong
Z
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China.
Ding
Lihua
L
Sun
Junzhong
J
Cao
Jia
J
Lin
Jing
J
Lu
Zhaohui
Z
Liu
Yufei
Y
Huang
Cuifen
C
Ye
Qinong
Q
D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D011960:Receptors, Estrogen; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D014157:Transcription Factors