ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer

Todd W. Miller, Justin M. Balko, Emily M. Fox, Zara Ghazoui, Anita Dunbier, Helen Anderson, Mitch Dowsett, Aixiang Jiang, R. Adam Smith, Sauveur Michel Maira, H. Charles Manning, Ana M. González-Angulo, Gordon B. Mills, Catherine Higham, Siprachanh Chanthaphaychith, Maria G. Kuba, William R. Miller, Yu Shyr, Carlos L. Arteaga

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    Abstract

    Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER+ xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers. SIGNIFICANCE: ERα retains genomic activity and drives a CDK4/E2Fdependent transcriptional program despite estrogen deprivation therapy. Combined inhibition of ER and PI3K induced regression of ER+ xenografts, supporting further development of strong ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for the treatment of antiestrogen- resistant breast cancers.

    Original languageEnglish (US)
    Pages (from-to)338-351
    Number of pages14
    JournalCancer discovery
    Volume1
    Issue number4
    DOIs
    StatePublished - Sep 1 2011

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    ASJC Scopus subject areas

    • Oncology

    Cite this

    Miller, T. W., Balko, J. M., Fox, E. M., Ghazoui, Z., Dunbier, A., Anderson, H., Dowsett, M., Jiang, A., Adam Smith, R., Maira, S. M., Charles Manning, H., González-Angulo, A. M., Mills, G. B., Higham, C., Chanthaphaychith, S., Kuba, M. G., Miller, W. R., Shyr, Y., & Arteaga, C. L. (2011). ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer discovery, 1(4), 338-351. https://doi.org/10.1158/2159-8290.CD-11-0101