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Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination

  • Preclinical study
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Abstract

ERα function is crucial for the 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 ERα and TGF-β down-stream molecules: SMAD2, SMAD3, and SMAD4, that can bind ERα and regulate their signaling. Thus, identification of natural anticancer drugs able to influence the latter molecule 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 ERα and on TGF-β pathway. We reported that bergapten, a coumarin containing compound, effectively depletes ERα in MCF-7 breast cancer sensitive cells and in tamoxifen-resistant clone. The decrease of ERα 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 ERα in both control and bergapten-treated cells, compared to wild- type cells. The same results were confirmed in siRNA TGF-β RII cells. The results suggest a novel negative regulation of ERα by TGF-β/SMAD4 in breast cancer cells and indicate that the SMAD4 protein is involved in the degradation of ERα induced by bergapten. We propose that bergapten may efficiently act as a natural antitumoral agent, able to deplete ERα from breast cancer tamoxifen-sensitive and resistant cells, thereby retraining the effect of membrane signals targeting ERα and in such way its mitogenic potentiality.

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Abbreviations

B:

Bergapten

5-MOP:

5-Methoxypsoralen

ERα:

Estrogen receptor α

TGF-β:

Trasforming growth factor beta

MAPK:

Mitogen-activated protein kinase

Poly Ub:

Poly-ubiquitin

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Acknowledgments

This study was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 2011, grant IG 11595) and PRIN grant 2008; we thank Dr. P. Cicirelli for technical assistance, University of Calabria, Cosenza.

Conflict of interest

The authors declare no conflict of interests.

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Authors and Affiliations

  1. Department of Cellular Biology, University of Calabria, Via P. Bucci, 87036, Arcavacata di Rende (CS), Italy

    M. L. Panno, F. Giordano, P. Rizza, M. Pellegrino, L. Mauro & S. Andò

  2. Health Center, University of Calabria, 87036, Arcavacata di Rende (CS), Italy

    C. Giordano, S. Catalano, S. Aquila, D. Sisci, F. De Amicis & S. Andò

  3. Department of Pharmaco-Biology, Faculty of Pharmacy, Nutritional and Health Science, University of Calabria, 87036, Arcavacata di Rende (CS), Italy

    D. Zito, S. Catalano, S. Aquila, D. Sisci, F. De Amicis, A. Vivacqua & S. Andò

  4. Lester and Sue Smith Breast Center, Breast Center, Baylor College of Medicine, Houston, TX, 77479, USA

    S. W. A. Fuqua

Authors
  1. M. L. Panno
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  2. F. Giordano
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  3. P. Rizza
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  4. M. Pellegrino
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  5. D. Zito
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  6. C. Giordano
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  7. L. Mauro
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  8. S. Catalano
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  9. S. Aquila
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  10. D. Sisci
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  11. F. De Amicis
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  12. A. Vivacqua
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  13. S. W. A. Fuqua
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  14. S. Andò
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Corresponding authors

Correspondence to M. L. Panno or S. Andò.

Additional information

M. L. Panno & F. Giordano contributed equally to this work.

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Panno, M.L., Giordano, F., Rizza, P. et al. Bergapten induces ER depletion in breast cancer cells through SMAD4-mediated ubiquitination. Breast Cancer Res Treat 136, 443–455 (2012). https://doi.org/10.1007/s10549-012-2282-3

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  • DOI: https://doi.org/10.1007/s10549-012-2282-3

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