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Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas

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Abstract

To explore mechanisms related to hormone resistance, three resistant variants of the MPA mouse breast cancer tumor model with low levels of progesterone receptor (PR) isoform A (PR-A)/high PR-B expression were developed by prolonged selective pressure with antiprogestins. The resistant phenotype of one tumor line was reversed spontaneously after several consecutive passages in syngeneic BALB/c mice or by 17-β-estradiol or tamoxifen treatment, and this reversion was significantly associated with an increase in PR-A expression. The responsive parental tumors disclosed low activation of ERK and high activation of AKT; resistant tumors on the other hand, showed the opposite, and this was associated with a higher metastatic potential, that did not revert. This study shows for the first time in vivo a relationship between PR isoform expression and antiprogestin responsiveness, demonstrating that, whereas acquired resistance may be reversed, changes in kinase activation and metastatic potential are unidirectional associated with tumor progression.

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Acknowledgements

We are grateful P. Do Campo for excellent technical assistance and to Laboratorios Gador, Buenos Aires for kindly providing MPA (Medrosterona) and TAM, and to Bayer Schering Pharma AG, Berlin for the ZK 230211. We also wish to thank Avon Foundation and AFLAC for AACR travel awards to V. Wargon. The authors declare that they have no competing interests.

Financial support

Sales Foundation, SECyT (PICT 03-14406 and PICT 05-15038) and CONICET (PIP 5351).

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  1. Luisa A. Helguero

    Present address: Department of Biosciences and Nutrition, Karolinska Institutet, 141 57, Stockholm, Sweden

  2. Alfredo Molinolo

    Present address: Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD, 20892-4340, USA

Authors and Affiliations

  1. Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Obligado 2490, 1428, Buenos Aires, Argentina

    Victoria Wargon, Luisa A. Helguero, Julieta Bolado, Paola Rojas, Virginia Novaro, Alfredo Molinolo & Claudia Lanari

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  1. Victoria Wargon
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Correspondence to Claudia Lanari.

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Wargon, V., Helguero, L.A., Bolado, J. et al. Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas. Breast Cancer Res Treat 116, 449–460 (2009). https://doi.org/10.1007/s10549-008-0150-y

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