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Resensitization of breast cancer cells to anoikis by Tropomyosin-1: role of Rho kinase-dependent cytoskeleton and adhesion

Abstract

Two most common properties of malignant cells are the presence of aberrant actin cytoskeleton and resistance to anoikis. Suppression of several key cytoskeletal proteins, including tropomyosin-1 (TM1), during neoplastic transformation is hypothesized to contribute to the altered cytoskeleton and neoplastic phenotype. Using TM1 as a paradigm, we have shown that cytoskeletal proteins induce anoikis in breast cancer (MCF-7 and MDA MB 231) cells. Here, we have tested the hypothesis that TM1-mediated cytoskeletal changes regulate integrin activity and the sensitivity to anoikis. TM1 expression in MDA MB 231 cells promotes the assembly of stress fibers, induces rapid anoikis via caspase-dependent pathways involving the release of cytochrome c. Further, TM1 inhibits binding of MDA MB 231 cells to collagen I, but promotes adhesion to laminin. Inhibition of Rho kinase disrupts TM1-mediated cytoskeletal reorganization and adhesion to the extracellular matrix components, whereas the parental cells attach to collagen I, spread and form extensive actin meshwork in the presence of Rho kinase inhibitor, underscoring the differences in parental and TM1-transduced breast cancer cells. Further, treatment with the cytoskeletal disrupting drugs rescues the cells from TM1-induced anoikis. These new findings demonstrate that the aberrant cytoskeleton contributes to neoplastic transformation by conferring resistance to anoikis. Restoration of stress fiber network through enhanced expression of key cytoskeletal proteins may modulate the activity of focal adhesions and sensitize the neoplastic cells to anoikis.

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Acknowledgements

This research is supported by an award from the Intramural Research Support Committee and the Department of General Surgery to GLP. GLP acknowledges the support of the Breast cancer research program from the Department of Defense (DAMD-98-1-8162). RF acknowledges the support of Associazione Italiana per la Ricerca sul Cancro (AIRC) and Ministero della Salute-Italy. We thank Ken Grant for the help with confocal microscopy, Stewart Roten for flow cytometry and Jerryann Weddle for technical assistance.

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Correspondence to G L Prasad.

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Bharadwaj, S., Thanawala, R., Bon, G. et al. Resensitization of breast cancer cells to anoikis by Tropomyosin-1: role of Rho kinase-dependent cytoskeleton and adhesion. Oncogene 24, 8291–8303 (2005). https://doi.org/10.1038/sj.onc.1208993

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Keywords

  • cytoskeleton
  • breast cancer
  • anoikis
  • adhesion
  • integrins
  • Rho kinase signaling
  • tropomyosin

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