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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Breast+Cancer+Res+Treat 2012 ; 136 (2): 443-55 Nephropedia Template TP
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Bergapten induces proteasome-dependent degradation of ER in breast cancer cells: Involvement of SMAD4 in the ubiquitination process #MMPMID23053665
Panno M; Giordano F; Rizza P; Pellegrino M; Zito M; Giordano C; Mauro L; Catalano S; Aquila A; Sisci D; De Amicis F; Vivacqua A; Fuqua S; Andō S
Breast Cancer Res Treat 2012[Nov]; 136 (2): 443-55 PMID23053665show ga
Introduction: ER? function is crucial for development of normal mammary gland as well as in the process of progression of breast cancer cells.Signals that target receptor levels contribute to regulate estrogens effects in the cells. An intricate cross-regulation has been documented between ER? and TGF-? down-stream molecules: SMAD2, SMAD3 and SMAD4, that can bind ER? and regulate their signaling. Thus, identification of natural anticancer drugs able to influence the latter effect might provide alternative choices for breast cancer treatment. Taking into account our previous published data we wanted to study the effect of 5-Methoxypsoralen (bergapten) on ER? and on TGF-? pathway. Methods: RT-PCR and W.B. were performed to evaluate the effect of bergapten on the ER? expression protein and the TGF-? ?down stream signaling molecules. siRNA for Smad4 and TGF- ? RII was also done to evaluate their involvement on the bergapten-induced responses. Results: We reported that bergapten, a coumarin containing compound, effectively depletes ER? in MCF-7 breast cancer sensitive cells and in tamoxifen-resistant clone. The decrease of ER? protein after bergapten treatment results from the ubiquitine-proteasome pathway as demonstrated by the use of MG-132. IP experiments with ER antibody, demonstrated that the protein has physical interaction with SMAD4 and poly-ubiquitine and the amount of ubiquitinated receptor, linked to SMAD4, is greater under bergapten. The crucial role played by SMAD4, in this process, emerges from the observation that in breast cancer cells, silencing of SMAD4, resulted in increased expression of endogenous ER? in both control and bergapten-treated cells, compared to wild type cells. The same results were confirmed in siRNA TGF-? RII cells. Conclusions: The results suggest a novel negative regulation of ER? by TGF-?/SMAD4 in breast cancer cells and indicate that the SMAD4 protein is involved in the degradation of ER? induced by bergapten. We propose that bergapten may efficiently act as a natural antitumoral agent, able to deplete ER? from breast cancer tamoxifen-sensitive and resistant cells, thereby retraining the effect of membrane signals targeting ER? and in such way its mitogenic potentiality.