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 Mills, Catherine Higham, Siprachanh Chanthaphaychith, Maria G. Kuba, William R. Miller, Yu Shyr, Carlos L. Arteaga

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Estrogen Receptors
Estrogens
Breast Neoplasms
Phosphatidylinositol 3-Kinase
Estrogen Receptor Modulators
Aromatase Inhibitors
Heterografts
Small Interfering RNA
Chromatin Immunoprecipitation
Gene Expression Profiling
Growth
Transcriptional Activation
Growth Hormone
Therapeutics
Down-Regulation

ASJC Scopus subject areas

  • Oncology

Cite this

Miller, T. W., Balko, J. M., Fox, E. M., Ghazoui, Z., Dunbier, A., Anderson, H., ... 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

ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. / Miller, Todd W.; Balko, Justin M.; Fox, Emily M.; Ghazoui, Zara; Dunbier, Anita; Anderson, Helen; Dowsett, Mitch; Jiang, Aixiang; Adam Smith, R.; Maira, Sauveur Michel; Charles Manning, H.; González-Angulo, Ana M.; Mills, Gordon; Higham, Catherine; Chanthaphaychith, Siprachanh; Kuba, Maria G.; Miller, William R.; Shyr, Yu; Arteaga, Carlos L.

In: Cancer Discovery, Vol. 1, No. 4, 01.09.2011, p. 338-351.

Research output: Contribution to journalArticle

Miller, TW, Balko, JM, Fox, EM, Ghazoui, Z, Dunbier, A, Anderson, H, Dowsett, M, Jiang, A, Adam Smith, R, Maira, SM, Charles Manning, H, González-Angulo, AM, Mills, G, Higham, C, Chanthaphaychith, S, Kuba, MG, Miller, WR, Shyr, Y & Arteaga, CL 2011, 'ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer', Cancer Discovery, vol. 1, no. 4, pp. 338-351. https://doi.org/10.1158/2159-8290.CD-11-0101
Miller, Todd W. ; Balko, Justin M. ; Fox, Emily M. ; Ghazoui, Zara ; Dunbier, Anita ; Anderson, Helen ; Dowsett, Mitch ; Jiang, Aixiang ; Adam Smith, R. ; Maira, Sauveur Michel ; Charles Manning, H. ; González-Angulo, Ana M. ; Mills, Gordon ; Higham, Catherine ; Chanthaphaychith, Siprachanh ; Kuba, Maria G. ; Miller, William R. ; Shyr, Yu ; Arteaga, Carlos L. / ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. In: Cancer Discovery. 2011 ; Vol. 1, No. 4. pp. 338-351.
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AU - Miller, Todd W.

AU - Balko, Justin M.

AU - Fox, Emily M.

AU - Ghazoui, Zara

AU - Dunbier, Anita

AU - Anderson, Helen

AU - Dowsett, Mitch

AU - Jiang, Aixiang

AU - Adam Smith, R.

AU - Maira, Sauveur Michel

AU - Charles Manning, H.

AU - González-Angulo, Ana M.

AU - Mills, Gordon

AU - Higham, Catherine

AU - Chanthaphaychith, Siprachanh

AU - Kuba, Maria G.

AU - Miller, William R.

AU - Shyr, Yu

AU - Arteaga, Carlos L.

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N2 - 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.

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