Skip to main content
Top

01-02-2017 | Original Paper

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

Authors: Marina Inés Flamini, Ivonne Denise Uzair, Gisela Erika Pennacchio, Flavia Judith Neira, Joselina Magali Mondaca, Fernando Dario Cuello-Carrión, Graciela Alma Jahn, Tommaso Simoncini, Angel Matías Sanchez

Published in: Discover Oncology | Issue 1/2017

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference Siegel R et al (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236CrossRefPubMed Siegel R et al (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236CrossRefPubMed
2.
go back to reference Stevanovic A, Lee P, Wilcken N (2006) Metastatic breast cancer. Aust Fam Physician 35(5):309–312PubMed Stevanovic A, Lee P, Wilcken N (2006) Metastatic breast cancer. Aust Fam Physician 35(5):309–312PubMed
3.
go back to reference Acconcia F, Barnes CJ, Kumar R (2006) Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells. Endocrinology 147(3):1203–1212CrossRefPubMed Acconcia F, Barnes CJ, Kumar R (2006) Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells. Endocrinology 147(3):1203–1212CrossRefPubMed
4.
go back to reference Wu X et al (2004) Focal adhesion kinase regulation of N-WASP subcellular localization and function. J Biol Chem 279(10):9565–9576CrossRefPubMed Wu X et al (2004) Focal adhesion kinase regulation of N-WASP subcellular localization and function. J Biol Chem 279(10):9565–9576CrossRefPubMed
5.
go back to reference Sanchez AM et al (2011) Estrogen receptor-{alpha} promotes endothelial cell motility through focal adhesion kinase. Mol Hum Reprod 17(4):219–226CrossRefPubMed Sanchez AM et al (2011) Estrogen receptor-{alpha} promotes endothelial cell motility through focal adhesion kinase. Mol Hum Reprod 17(4):219–226CrossRefPubMed
6.
go back to reference McLean GW et al (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5(7):505–515CrossRefPubMed McLean GW et al (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5(7):505–515CrossRefPubMed
7.
go back to reference Sanchez AM et al (2010) Estrogen receptor-alpha promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP. Mol Endocrinol 24(11):2114–2125CrossRefPubMed Sanchez AM et al (2010) Estrogen receptor-alpha promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP. Mol Endocrinol 24(11):2114–2125CrossRefPubMed
8.
go back to reference Sanchez AM et al (2013) Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation. Mol Endocrinol 27(4):693–702CrossRefPubMed Sanchez AM et al (2013) Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation. Mol Endocrinol 27(4):693–702CrossRefPubMed
9.
go back to reference Fu XD et al (2010) Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase. Endocr Relat Cancer 17(2):431–443CrossRefPubMed Fu XD et al (2010) Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase. Endocr Relat Cancer 17(2):431–443CrossRefPubMed
10.
go back to reference van Nimwegen MJ, van de Water B (2007) Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol 73(5):597–609CrossRefPubMed van Nimwegen MJ, van de Water B (2007) Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol 73(5):597–609CrossRefPubMed
12.
go back to reference Zhao J, Guan JL (2009) Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 28(1–2):35–49CrossRefPubMed Zhao J, Guan JL (2009) Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev 28(1–2):35–49CrossRefPubMed
13.
go back to reference Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562CrossRefPubMed Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9(8):550–562CrossRefPubMed
14.
go back to reference Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6(10):587–595CrossRefPubMed Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6(10):587–595CrossRefPubMed
15.
go back to reference Flamini MI et al (2011) Estrogen regulates endometrial cell cytoskeletal remodeling and motility via focal adhesion kinase. Fertil Steril 95(2):722–726CrossRefPubMed Flamini MI et al (2011) Estrogen regulates endometrial cell cytoskeletal remodeling and motility via focal adhesion kinase. Fertil Steril 95(2):722–726CrossRefPubMed
16.
go back to reference Luo M, Guan JL (2010) Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett 289(2):127–139CrossRefPubMed Luo M, Guan JL (2010) Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett 289(2):127–139CrossRefPubMed
17.
go back to reference Arold ST (2011) How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. Curr Opin Struct Biol 21(6):808–813CrossRefPubMedPubMedCentral Arold ST (2011) How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. Curr Opin Struct Biol 21(6):808–813CrossRefPubMedPubMedCentral
19.
go back to reference Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18(5):516–523CrossRefPubMed Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18(5):516–523CrossRefPubMed
20.
go back to reference Vultur A et al (2008) SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7(5):1185–1194CrossRefPubMedPubMedCentral Vultur A et al (2008) SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7(5):1185–1194CrossRefPubMedPubMedCentral
21.
go back to reference McLean BA et al (2013) PI3K inhibitors as novel cancer therapies: implications for cardiovascular medicine. J Card Fail 19(4):268–282CrossRefPubMed McLean BA et al (2013) PI3K inhibitors as novel cancer therapies: implications for cardiovascular medicine. J Card Fail 19(4):268–282CrossRefPubMed
22.
go back to reference Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4):257–262CrossRefPubMed Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4):257–262CrossRefPubMed
23.
go back to reference Stephens L, Williams R, Hawkins P (2005) Phosphoinositide 3-kinases as drug targets in cancer. Curr Opin Pharmacol 5(4):357–365CrossRefPubMed Stephens L, Williams R, Hawkins P (2005) Phosphoinositide 3-kinases as drug targets in cancer. Curr Opin Pharmacol 5(4):357–365CrossRefPubMed
24.
25.
go back to reference Moeller LC, Fuhrer D (2013) Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer 20(2):R19–R29CrossRefPubMed Moeller LC, Fuhrer D (2013) Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer 20(2):R19–R29CrossRefPubMed
26.
go back to reference Ditsch N et al (2013) Thyroid hormone receptor (TR)alpha and TRbeta expression in breast cancer. Histol Histopathol 28(2):227–237PubMed Ditsch N et al (2013) Thyroid hormone receptor (TR)alpha and TRbeta expression in breast cancer. Histol Histopathol 28(2):227–237PubMed
27.
go back to reference Cristofanilli M et al (2005) Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103(6):1122–1128CrossRefPubMed Cristofanilli M et al (2005) Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103(6):1122–1128CrossRefPubMed
28.
go back to reference Tosovic A et al (2010) Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 12(3):R33CrossRefPubMedPubMedCentral Tosovic A et al (2010) Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 12(3):R33CrossRefPubMedPubMedCentral
29.
go back to reference Hercbergs AH, Ashur-Fabian O, Garfield D (2010) Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 17(5):432–436CrossRefPubMed Hercbergs AH, Ashur-Fabian O, Garfield D (2010) Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 17(5):432–436CrossRefPubMed
30.
go back to reference Furuya F et al (2009) Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors. Steroids 74(7):628–634CrossRefPubMed Furuya F et al (2009) Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors. Steroids 74(7):628–634CrossRefPubMed
31.
go back to reference Kavok NS, Krasilnikova OA, Babenko NA (2001) Thyroxine signal transduction in liver cells involves phospholipase C and phospholipase D activation. Genomic independent action of thyroid hormone. BMC Cell Biol 2:5CrossRefPubMedPubMedCentral Kavok NS, Krasilnikova OA, Babenko NA (2001) Thyroxine signal transduction in liver cells involves phospholipase C and phospholipase D activation. Genomic independent action of thyroid hormone. BMC Cell Biol 2:5CrossRefPubMedPubMedCentral
33.
go back to reference Flamini, M.I., et al. 2014 Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta. J Cell Mol Med Flamini, M.I., et al. 2014 Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta. J Cell Mol Med
34.
go back to reference Lin HY et al (1999) Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am J Phys 276(5 Pt 1):C1014–C1024 Lin HY et al (1999) Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am J Phys 276(5 Pt 1):C1014–C1024
35.
go back to reference Lin HY et al (2009) L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296(5):C980–C991CrossRefPubMed Lin HY et al (2009) L-thyroxine vs. 3,5,3′-triiodo-L-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296(5):C980–C991CrossRefPubMed
36.
go back to reference Desgrosellier JS et al (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15(10):1163–1169CrossRefPubMedPubMedCentral Desgrosellier JS et al (2009) An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med 15(10):1163–1169CrossRefPubMedPubMedCentral
37.
go back to reference Meng R et al (2011) Crosstalk between integrin alphavbeta3 and estrogen receptor-alpha is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One 6(11):e27547CrossRefPubMedPubMedCentral Meng R et al (2011) Crosstalk between integrin alphavbeta3 and estrogen receptor-alpha is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One 6(11):e27547CrossRefPubMedPubMedCentral
39.
40.
go back to reference Goodman AD, Hoekstra SJ, Marsh PS (1980) Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res 40(7):2336–2342PubMed Goodman AD, Hoekstra SJ, Marsh PS (1980) Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res 40(7):2336–2342PubMed
42.
go back to reference Zhang J, Lazar MA (2000) The mechanism of action of thyroid hormones. Annu Rev Physiol 62:439–466CrossRefPubMed Zhang J, Lazar MA (2000) The mechanism of action of thyroid hormones. Annu Rev Physiol 62:439–466CrossRefPubMed
43.
go back to reference Freindorf M et al (2012) Combined QM/MM study of thyroid and steroid hormone analogue interactions with alphavbeta3 integrin. J Biomed Biotechnol 2012:959057CrossRefPubMedPubMedCentral Freindorf M et al (2012) Combined QM/MM study of thyroid and steroid hormone analogue interactions with alphavbeta3 integrin. J Biomed Biotechnol 2012:959057CrossRefPubMedPubMedCentral
44.
go back to reference Davis PJ et al (2011) Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol 51:99–115CrossRefPubMed Davis PJ et al (2011) Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu Rev Pharmacol Toxicol 51:99–115CrossRefPubMed
46.
go back to reference Cohen, K., et al. 2014 Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via alphavbeta3 integrin in myeloma cells. Oncotarget Cohen, K., et al. 2014 Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via alphavbeta3 integrin in myeloma cells. Oncotarget
47.
go back to reference Reiske HR et al (1999) Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J Biol Chem 274(18):12361–12366CrossRefPubMed Reiske HR et al (1999) Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. J Biol Chem 274(18):12361–12366CrossRefPubMed
48.
go back to reference Thamilselvan V, Craig DH, Basson MD (2007) FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway. FASEB J 21(8):1730–1741CrossRefPubMed Thamilselvan V, Craig DH, Basson MD (2007) FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway. FASEB J 21(8):1730–1741CrossRefPubMed
49.
go back to reference Leonard JL, Farwell AP (1997) Thyroid hormone-regulated actin polymerization in brain. Thyroid 7(1):147–151CrossRefPubMed Leonard JL, Farwell AP (1997) Thyroid hormone-regulated actin polymerization in brain. Thyroid 7(1):147–151CrossRefPubMed
51.
Metadata
Title
Thyroid Hormone Controls Breast Cancer Cell Movement via Integrin αV/β3/SRC/FAK/PI3-Kinases
Authors
Marina Inés Flamini
Ivonne Denise Uzair
Gisela Erika Pennacchio
Flavia Judith Neira
Joselina Magali Mondaca
Fernando Dario Cuello-Carrión
Graciela Alma Jahn
Tommaso Simoncini
Angel Matías Sanchez
Publication date
01-02-2017
Publisher
Springer US
Published in
Discover Oncology / Issue 1/2017
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI
https://doi.org/10.1007/s12672-016-0280-3