The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

Emily E. Bosco, Ying Wang, Huan Xu, Jack T. Zilfou, Karen E. Knudsen, Bruce J. Aronow, Scott W. Lowe, Erik S. Knudsen

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139 Scopus citations

Abstract

The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G1/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.

Original languageEnglish (US)
Pages (from-to)218-228
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number1
DOIs
StatePublished - Jan 4 2007

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bosco, E. E., Wang, Y., Xu, H., Zilfou, J. T., Knudsen, K. E., Aronow, B. J., Lowe, S. W., & Knudsen, E. S. (2007). The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. Journal of Clinical Investigation, 117(1), 218-228. https://doi.org/10.1172/JCI28803