Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases

Abstract

Thyroid hormones (TH) play a fundamental role in diverse processes, including cellular movement. Cell migration requires the integration of events that induce changes in cell structure towards the direction of migration. These actions are driven by actin remodeling and stabilized by the development of adhesion sites to extracellular matrix via transmembrane receptors linked to the actin cytoskeleton. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that promotes cell migration and invasion through the control of focal adhesion turnover. In this work, we demonstrate that the thyroid hormone triiodothyronine (T3) regulates actin remodeling and cell movement in breast cancer T-47D cells through the recruitment of FAK. T3 controls FAK phosphorylation and translocation at sites where focal adhesion complexes are assembled. This process is triggered via rapid signaling to integrin αV/β3, Src, phosphatidylinositol 3-OH kinase (PI3K), and FAK. In addition, we established a cellular model with different concentration of T3 levels: normal, absence, and excess in T-47D breast cancer cells. We found that the expression of Src, FAK, and PI3K remained at normal levels in the excess of T3 model, while it was significantly reduced in the absence model. In conclusion, these results suggest a novel role for T3 as an important modulator of cell migration, providing a starting point for the development of new therapeutic strategies for breast cancer treatment.

Cytoplasmic and Nuclear Forms of Thyroid Hormone Receptor β1 Are Inversely Associated with Survival in Primary Breast Cancer

“…It is also known that THR can be present not only in the nucleus, but also in the cytoplasm and in the mitochondria [12]. T3 can also be associated to plasma membrane structural α5β3 integrin, thereby regulating cell-cell and cell-extracellular matrix interactions and changing the morphology of BC cells [36]. Our results are supported by a previous study reporting cytoplasmic expression of THRβ1.…”

Dynamic membrane proteome of adipogenic and myogenic precursors in skeletal muscle highlights EPHA2 may promote myogenic differentiation through ERK signaling

“…For example, thyroid hormone (TH) plays an essential role in myogenesis, and T3 stimulated myoblast differentiation through the activation of TH receptor α and followed by Wnt/β signaling pathway ( 48 ). Although the role of integrin in TH-mediated cell migration has been described ( 49 ), the function of integrins identified in this study, such as ITBG3 and ITGAV, in TH-mediated myogenic differentiation was not clear. We supposed that ITGB3 and ITGAV might accept the stimulation of TH and transduce this signal to control myogenic differentiation via several intrinsic factors.…”

<p>Downregulation of OSR1 Promotes Colon Adenocarcinoma Progression via FAK-Mediated Akt and MAPK Signaling</p>

“…Activated FAK stimulates the downstream kinase PI3K by binding and phosphorylating the p85α subunit of PI3K (regulatory subunit of PI3K). 22 As a downstream signaling pathway of FAK activation, PI3K/AKT could regulate cancer cell proliferation, migration, apoptosis, cell cycle, and survival. 14,[23][24][25] AKT activation could upregulate cyclin D1 14 and c-Myc, 26 and downregulate cyclin D kinase (CDK) inhibitors p21.…”