Endocrine Abstracts

Objective: Mesenchymal stem cells (MSCs) are central players and the most abundant cell type in the breast cancer tumor microenvironment and own a well-recognized role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment, making them attractive novel targets for anti-tumor therapy. There is increasing evidence for an association between thyroid function and breast cancer risk, and thyroid hormone- mediated effects through the αvβ3 integrin are proposed as a pathophysiologic link.

Methods: To evaluate the migration behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different types of breast cancer cells (T47D, MCF7, BT-474, MB-231, MB- 453).

Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed a directed chemotaxis towards tumor-CM with significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. Except for T47D-CM, the additional treatment with tetrac inhibited the effects of T3 and T4 on MSC migration, demonstrating that this effect is mediated through αvβ3 integrin.

Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and thyroid hormone metabolite tetrac on MSC migration suggest an important role of non- genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation.