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Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts

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Abstract

Resistance to endocrine therapy is a major complication of luminal breast cancer and studies of the biological features of hormonal resistance are limited by the lack of adequate preclinical models. The aim of this study is to establish and characterize a panel of primary human luminal breast carcinoma xenografts, and to evaluate their response to endocrine therapies. Four hundred and twenty-three tumor fragments obtained directly from patients have been grafted in the interscapular fatpad of Swiss nude mice. After stable engraftment with estradiol supplementation, xenografted tumors have been validated by conventional pathology and immunohistochemistry examination, and additional molecular studies. In vivo tumor growth and response to different endocrine treatments were evaluated. We have engrafted 423 tumors including 314 ER+ tumors, and 8 new luminal breast cancer xenografts have been obtained (2.5%). Tumor take was much lower for luminal tumors than for non-luminal tumors (2.5 vs. 24.7%, P < 0.0001), and was associated with two independent criteria, i.e., ER status (P < 0.0001) and a high grade tumor (P = 0.05). Histological and immunohistochemical analyses performed on patient’s tumors and xenografts showed striking similarities in the tumor morphology as well as in the expression level of ER, PR, and HER2. Response to hormone therapy, evaluated in 6 luminal models, showed different sensitivities, thus exhibiting heterogeneity similar to what is observed in the clinic. We have established a panel of primary human luminal breast cancer xenografts, recapitulating the biological and clinical behaviors of patient tumors, and therefore suitable for further preclinical experiments.

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Acknowledgments

We are especially indebted to all the patients who consented to give their tumors for animal experiments. We would also like to thank all the members of the surgical oncology, and tumor biology teams who devoted much time to the patient tumor sampling. We deeply thank O. Chouchane and A. Nicolas for the IHC pictures. The Institut Curie in vivo experiment platform members should be gratefully acknowledged for their invaluable contribution to the mouse care. We are also indebted to C. Tran-Perennou and C. Barbaroux who performed the qPCR analyses. This work was supported by the Translational Research Department of Institut Curie. Dr. Paul Cottu is supported by a Grant from the Institut Curie Foundation.

Conflict of interest

All authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Medical Oncology, Institut Curie, 26 Rue d’Ulm, 75005, Paris, France

    P. Cottu, P. Boudou-Rouquette & D. Decaudin

  2. Laboratory of Preclinical Investigations, Institut Curie Translational Research Department, Hôpital St Louis, Quadrilatère historique, Porte 13, 1, Ave Claude Vellefaux, 75010, Paris, France

    P. Cottu, E. Marangoni, F. Assayag, Ch. Guyader, L. de Plater, C. Elbaz, N. Karboul, V. Dangles-Marie, M.-F. Poupon & D. Decaudin

  3. Department of Pathology and Tumor Biology, Institut Curie, 26 Rue d’Ulm, 75005, Paris, France

    P. de Cremoux & A. Vincent-Salomon

  4. Pathology Department, Ecole Nationale Vétérinaire d’Alfort, 7, Ave du General de Gaulle, 94704, Maisons Alfort, France

    J. J. Fontaine & S. Chateau-Joubert

  5. Department of Surgical Oncology, Institut Curie, 26 Rue d’Ulm, 75005, Paris, France

    S. Alran

  6. Molecular Biology Facilities, Institut Curie Translational Research Department, Hôpital St Louis, 1, Ave Claude Vellefaux, 75010, Paris, France

    D. Gentien

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  1. P. Cottu
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  2. E. Marangoni
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  10. J. J. Fontaine
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  11. S. Chateau-Joubert
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  14. V. Dangles-Marie
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  17. D. Decaudin
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Corresponding authors

Correspondence to P. Cottu or D. Decaudin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary description of mice management according to ARRIVE guidelines (DOC 25 kb)

Supplementary Materials and methods data (DOC 48 kb)

Supplementary Table 1

Clinical characteristics of the 8 patients with xenografts (DOC 41 kb)

Supplementary Table 2

Actual mean volumes in each treatment groups in all reported experiments. (XLS 19 kb)

Supplementary Fig. 6

Extensive results of endocrine therapy testing on luminal xenografts. The figures show the response curves to endocrine therapies in tested models. In all figures, error bars were omitted for the sake of legibility. a Sensitivity to tamoxifen of the HBCx-3 model. b Extended therapeutic characterization of HBCx-3. The experiment is at a too early stage for P values. c Therapeutic characterization of HBCx-22. Specific P values are: tamoxifen <0.001; fulvestrant <0.001; d Extended therapeutic characterization of HBCx-22. Specific P values for endocrine treatments curves versus control are: ovariectomy = 0.19; ovariectomy + letrozole = 0.02; letrozole = 0.04; tamoxifen = 0.01; 4-OH-tamoxifen = 0.03. e Detailed view of selected groups from (d). f Therapeutic characterization of HBCx-34. Specific P values are: ovariectomy <0.001; fulvestrant <0.001; tamoxifen = 0.03 (PDF 58 kb)

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Cottu, P., Marangoni, E., Assayag, F. et al. Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts. Breast Cancer Res Treat 133, 595–606 (2012). https://doi.org/10.1007/s10549-011-1815-5

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  • DOI: https://doi.org/10.1007/s10549-011-1815-5

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