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Int. J. Mol. Sci. 2017, 18(7), 1574; doi:10.3390/ijms18071574

TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b

1
Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover 30625, Germany
2
Department of General and Thoracic Surgery, Universitatsklinikum Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
Theses authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 21 June 2017 / Revised: 14 July 2017 / Accepted: 16 July 2017 / Published: 20 July 2017
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Abstract

Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-β can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human mammary epithelial cells (HMEC). Moreover, TGF-β also drives cell migration and invasion, in part through the small GTPases Rac1 and Rac1b. Depletion of Rac1b or Rac1 and Rac1b in MDA-MB-231 or MDA-MB-435s breast cancer cells by RNA interference enhanced or suppressed, respectively, TGF-β1-induced migration/invasion. Rac1b depletion in MDA-MB-231 cells also increased TGF-β-induced p21WAF1 expression and ERK1/2 phosphorylation. Senescent HMEC (P15/P16), when compared to their non-senescent counterparts (P11/P12), presented with dramatically increased migratory activity. These effects were paralleled by elevated expression of genes associated with TGF-β signaling and metastasis, downregulated Rac1b, and upregulated Rac1. Our data suggest that acquisition of a motile phenotype in HMEC resulted from enhanced autocrine TGF-β signaling, invasion/metastasis-associated gene expression, and a shift in the ratio of antimigratory Rac1b to promigratory Rac1. We conclude that although enhanced TGF-β signaling is considered antioncogenic in HMEC by suppressing oncogene-induced transformation, this occurs at the expense of a higher migration and invasion potential. View Full-Text
Keywords: breast cancer; HMEC; cell cycle arrest; senescence; transforming growth factor-β breast cancer; HMEC; cell cycle arrest; senescence; transforming growth factor-β
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Melzer, C.; von der Ohe, J.; Hass, R.; Ungefroren, H. TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b. Int. J. Mol. Sci. 2017, 18, 1574.

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