Although both thyroid disease and breast cancer (BC) are more prevalent in women, the relationship between thyroid status and BC remains unclear. Previously, we demonstrated that hyperthyroid mice inoculated with 4T1 BC cells exhibit a higher tumor growth rate compared to euthyroid mice, whereas hypothyroid mice display a slower tumor growth rate but an increased number of lung metastases.
This study aimed to evaluate the mechanisms by which thyroid status modulates metastasis formation in BC. First, we treated 4T1 cells in vitro with triiodothyronine (T3) and thyroxine (T4) and assessed their migration using a wound-healing assay. The results indicated no direct effects of thyroid hormones on cell migration.
To further investigate the effects of thyroid status on BC metastasis formation in vivo, Balb/c mice were treated with T4 for 4 weeks (hyperthyroid, hyper), propylthiouracil (PTU) for 2 weeks (hypothyroid, hypo), or PTU for 2 weeks followed by daily injections of T3 for the last six days (reverted mice). The animals were then inoculated with 4T1 cells either orthotopically or intravenously (i.v).
Primary tumors from hypo mice showed increased levels of CXCL-16, CCL-5, and CCL-2 chemokines, which are involved in tumor cell migration. Additionally, hypo mice showed an increased proportion of myeloid-derived suppressor cells (MDSCs) in the lungs, which reverted to euthyroid levels upon T3 treatment. In contrast, hyper mice exhibited an increased proportion of cytotoxic T lymphocytes and B lymphocytes in the lungs. Hyper mice i.v. inoculated with 4T1 cells showed increased levels of NK cells, while hypo mice displayed higher levels of MDSCs. Furthermore, higher activity of matrix metalloproteinase-2 was detected in the lungs of hypo mice.
Our results suggest that thyroid status does not directly affect BC cell migration but significantly influences the antitumor immune response in the lungs, thereby affecting the metastatic potential of tumor cells.