Sven Rottenberg

Institution: Institute of Animal Pathology / Vetsuisse - University of Bern

Address:

Längassstr. 122 3012 Bern

Email: sven.rottenberg@vetsuisse.unibe.ch

Group website: under development

Phone: +41 (0)31 6312395

Research interests:

- Genetically engineered mouse models for breast cancer - Mechanisms of anti-cancer therapy resistance - PARP inhibitors - BRCA1, BRCA2, DNA repair - membrane transporters - minimal residual disease

Selected publications:

1. Xu G, Chapman RJ, Brandsma I, Yuan J, Mistrik M, Bouwman P, Bartkova J, Gogola E, Warmerdam D, Barazas M, Jaspers JE, Watanabe K, Pieterse M, Kersbergen A, Sol W, Celie PHN, Schouten PC, van den Broek B, Salman A, Nieuwland M, de Rink I, de Ronde J, Jalink K, Boulton SJ, Chen J, van Gent DC, Bartek J, Jonkers J, Borst P, Rottenberg S (2015). REV7 counteracts DNA double-strand break resection and affects PARP inhibition, Nature 521:541-4. This article describes the identification of a new mechanism of drug resistance and provides novel insights into basic DNA repair mechanisms. 2. Jaspers JE, Sol W, Kersbergen A, Schlicker A, Guyader C, Xu G, Wessels L, Borst P, Jonkers J, Rottenberg S (2015). BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance. Cancer Research 75:732-41. We show for the first time that drug efflux contributes to the resistance of mouse mammary tumors that underwent epithelial-to-mesenchymal transition. 3. Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, Drost R, Wientjens E, Ji J, Aly A, Doroshow JH, Cranston A, Martin NM, Lau A, O'Connor MJ, Ganesan S, Borst P, Jonkers J, Rottenberg S (2013). Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discovery 3:68-81. The article provides first evidence that loss of 53BP1 occurs in vivo and causes PARP inhibitor resistance. 4. Rottenberg S, Vollebergh MA, de Hoon B, de Ronde J, Schouten PC, Kersbergen A, Zander SA, Pajic M, Jaspers JE, Jonkers M, Lodén M, Sol W, Burg E, Wesseling J, Gillet JP, Gottesman MM, Gribnau J, Wessels L, Linn SC, Jonkers J, Borst P (2012). Impact of intertumoral heterogeneity on predicting chemotherapy response of BRCA1-deficient mammary tumors. Cancer Research 72, 2350-61. Here we show why standard algorithms to analyze gene expression data fail to identify predictive markers, and we developed an alternative analysis algorithm. In particular we find a predictive marker for cisplatin in BRCA1-mutated breast cancer. 5. Zander SA, Kersbergen A, van der Burg E, de Water N, van Tellingen O, Gunnarsdottir S, Jaspers JE, Pajic M, Nygren AO, Jonkers J, Borst P, Rottenberg S (2010). Sensitivity and acquired resistance of BRCA1;P53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Research 70, 1700-10. In this article we elucidate in vivo resistance mechanisms against the topoisomerase I inhibitor topotecan. 6. Pajic M, Iyer JK, Kersbergen A, van der Burg E, Nygren AO, Jonkers J, Borst P, Rottenberg S (2009). Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer. Cancer Research 69, 6396-404. Here we show that even a moderate increase in the gene expression of drug efflux transporters is sufficient to cause drug resistance 7. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J (2008). High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proceedings of the National Academy of Science U S A (PNAS) 105, 17079-17084. This is the first report that the concept of “synthetic lethality” works for PARP inhibitors in a mouse model for BRCA1-deficient breast cancer. It also provides a regimen for the use of PARP inhibitors in combination with platinum drugs, which is now used in the clinic. 8. Rottenberg S, Nygren AO, Pajic M, van Leeuwen FW, van der Heijden I, van de Wetering K, Liu X, de Visser KE, Gilhuijs KG, van Tellingen O, Schouten JP, Jonkers J, Borst P (2007). Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proceedings of the National Academy of Science U S A (PNAS) 104, 12117-12122. This is the first report that shows the usefulness of genetically engineered mouse models to study anti-cancer drug resistance mechanisms. In particular it shows the hypersensitivity of BRCA1-deficient tumors to platinum drugs.

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