Thyroid status regulates the tumor microenvironment delineating breast cancer fate

in Endocrine-Related Cancer
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  • 1 Neuroimmunomodulation and Molecular Oncology Laboratory, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
  • 2 Remodeling Processes and Cellular Niches Laboratory, Institute of Translational Medicine and Biomedical Engineering (IMTIB), National Scientific and Technical Research Council (CONICET), Italian Hospital of Buenos Aires and the University Institute of the Italian Hospital (IUHI), Buenos Aires, Argentina
  • 3 Immunobiology Department, Investigation Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires (UBA), National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
  • 4 Laboratory of Tumor Biology and Inflammation, Institute for Biomedical Research (BIOMED), School of Medical Sciences, Pontifical Catholic University of Argentina (UCA), and the National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina

Correspondence should be addressed to G A Cremaschi: graciela_cremaschi@uca.edu.ar
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The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple-negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed an increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens but increased activated CD8+ cells and the IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. A better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

Supplementary Materials

    • Supplementary Materials and Methods
    • Supplementary Table 1. List of antibodies used for flow cytometry analysis.
    • Supplementary Figure 1 Modulation of LM3 breast tumor growth and dissemination by thyroid status. Euthyroid (control), hyperthyroid (hyper) and hypothyroid (hypo) Balb/c mice were orthotopically inoculated with 1x105 LM3 cells (from a Balb/c mammary adenocarcinoma), as described in the “materials and methods” section. (A) Timecourse increase in tumor volume among the three experimental groups (n=9-11 mice per group). (B) Number of metastatic foci in lungs at day 40 post inoculation (p.i.) (n=9-11 mice per group). (C) Number of metastatic foci in lungs after 40 days of intravenous (i.v.) injection of 1x105 LM3 cells (n=7-8 mice per group).
    • Supplementary Figure 2 Modulation of LM3 breast tumor growth and dissemination by thyroid status. Euthyroid (control), hyperthyroid (hyper) and hypothyroid (hypo) Balb/c mice were orthotopically inoculated with 1x105 LM3 cells (from a Balb/c mammary adenocarcinoma), as described in the “materials and methods” section. (A) Timecourse increase in tumor volume among the three experimental groups (n=9-11 mice per group). (B) Number of metastatic foci in lungs at day 40 post inoculation (p.i.) (n=9-11 mice per group). (C) Number of metastatic foci in lungs after 40 days of intravenous (i.v.) injection of 1x105 LM3 cells (n=7-8 mice per group).

 

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