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DNA Methylation and Histone Deacetylation Inhibitors as Potential Therapeutic Agents for the Reconstitution of TGF-β Signaling in Breast Cancer

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Transforming Growth Factor-β in Cancer Therapy, Volume II

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Neoplastic cells show reduced expression of TGF-β receptor type II (RII) in comparison to the normal breast tissue and benign lesions. Also, loss of RII expression correlates with high-tumor grade and invasive carcinomas. This correlation is also reflected in established primary breast carcinoma cell lines. Absence/reduced expression of RII was not associated with RII gene deletion, amplification, or mutations. The RII promoter is devoid of a distinct TATA box and is dependent on Sp1 transcription factor for its activity. While Sp1 activates RII gene transcription another member of the Sp gene family, Sp3 acts as a repressor, thus suggesting SP1/Sp3 activities control RII gene expression. Loss of RII expression in breast cancer cells involves two epigenetic mechanisms, DNA methylation and histone deacetylation. Inhibition of DNA methylation by decitabine (5 aza 2′ deoxycytidine) stimulated RII expression in breast cancer cells. However, loss of RII expression was not owing to methylation of the RII gene. The RII gene in breast cancer cells exhibited reduced Sp1 binding and increased Sp3 binding activities. Inhibition of DNA methylation led to increased Sp1 binding as a consequence of increased Sp1 protein stability and simultaneous loss of Sp3 binding owing to decreased Sp3 transcription, thus altering Sp1/Sp3 activities leading to RII expression in breast cancer cells. In contrast, inhibition of histone deacetylation by trichostatin A (TSA) induced RII expression without changing activator Sp1 and repressor Sp3 binding activities. However, in the TSA treated breast cancer cells, histone acetyltransferase (HATs) p300 mediated acetylation of Sp3 and converted Sp3 from a repressor to an activator of RII gene transcription. RII regeneration following inhibition of DNA methylation as well as histone deacetylation restored TGF-β response, thus suggesting that DNA methylation inhibitor decitabine and histone deacetylation inhibitor TSA either alone or in combination may be used as potential therapeutic agents for the reconstitution of TGF-β tumor suppressor pathway in breast carcinomas.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, The University of Texas Health Science Center, San Antonio, TX, USA

    Sudhakar Ammanamanchi PhD

  2. Eppley Institute, University of Nebraska Medical Center, Omaha, NE, USA

    Michael G. Brattain PhD

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  1. Sudhakar Ammanamanchi PhD
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  2. Michael G. Brattain PhD
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  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

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© 2008 Humana Press Inc., Totowa, NJ

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Ammanamanchi, S., Brattain, M.G. (2008). DNA Methylation and Histone Deacetylation Inhibitors as Potential Therapeutic Agents for the Reconstitution of TGF-β Signaling in Breast Cancer. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_29

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  • DOI: https://doi.org/10.1007/978-1-59745-293-9_29

  • Publisher Name: Humana Press

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