ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer
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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/E2F-dependent 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. Cancer Discovery; 1(4); 338–51. ©2011 AACR. Read the Commentary on this article by Van Tine et al., p. 287 This article is highlighted in the In This Issue feature, p. 275
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Higher CDK4 expression drives endocrine therapy resistance in HR-positive breast cancer patients.
“Increased expression of CDK4 has been shown to drive resistance to endocrine therapy in patients with HR-positive breast cancer. 4-7”
From Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. (2022) · cites this paper as [7]
The Results section on CDK4 reports that CDK4 knockdown or CDK4/6 inhibition suppressed hormone-independent growth in ER-positive breast cancer cell lines. The patient-tumor findings instead link an E2F activation signature—not higher CDK4 expression—to poorer response to aromatase inhibitors. The paper therefore supports a role for CDK4 in a resistance-related pathway, but does not show that increased CDK4 expression drives endocrine resistance in patients. (LLM, conf=0.88)
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- Authors
- Miller, T. W., Balko, J. M., Fox, E. M., Ghazoui, Z., Dunbier, A., Anderson, H., Dowsett, M., Jiang, A., Smith, R. A., Maira, S.-M., Manning, H. C., González-Angulo, A. M., Mills, G. B., Higham, C., Chanthaphaychith, S., Kuba, M. G., Miller, W. R., Shyr, Y., & Arteaga, C. L.
- Affiliations
- Novartis (Switzerland) (CH)
- Institute of Cancer Research (GB)
- Authors' Affiliations: Departments of 1Cancer Biology, 2Medicine, 3Biostatistics, 4Radiology and Radiological Sciences, and 5Pathology; 6Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center; 7Institute of Imaging Sciences, Vanderbilt University, Nashville, Tennessee; 8Breakthrough Breast Cancer Centre, Institute of Cancer Research, and 9Academic Department of Biochemistry, Royal Marsden Hospital, London, UK; 10Novartis Institute for Biomedical Research, Oncology Disease Area, Basel, Switzerland; Departments of 11Breast Medical Oncology and 12Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 13Breast Research Group, University of Edinburgh, Edinburgh, UK
- Corresponding author
- Arteaga, Carlos L.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2011-09-01
- Volume
- 1
- Issue
- 4
- Pages
- 338-351
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3204388
- OpenAlex
- W2033672070
- Cited by
- 346
- References
- 51
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 18 · 2023: 18 · 2022: 21 · 2021: 43 · 2020: 27 · 2019: 20 · 2018: 25 · 2017: 38 · 2016: 27 · 2015: 29 · 2014: 26 · 2013: 19 · 2012: 5
- FWCI
- 10.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Breast Cancer Research Foundation
- Vanderbilt University
- Vanderbilt Institute for Clinical and Translational Research
- Vanderbilt-Ingram Cancer Center (P30 CA 68485)
- National Institutes of Health (5r01ca140628-05, R01CA140628)
- National Cancer Institute (P50 CA98131, R01-CA140628, P30 CA 68485, F32CA121900, P50CA098258, R01CA080195, K99CA142899, K25CA127349, P50CA098131, U24CA126588, T32CA009592, P30CA068485, RC1CA145138)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- estrogen receptor alpha, E2F transcription, CDK4, Rb, estrogen-independent breast cancer, aromatase inhibitor resistance, fulvestrant, phosphatidylinositol 3-kinase, BKM120, CDK4 inhibitors, hormone-independent growth, combination therapy
- MeSH terms
- Animals, Breast Neoplasms, Estrogens, Female, Humans, Mice, Nude, Transcription, Genetic, Down-Regulation, Gene Expression, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Estrogen Receptor Modulators, Cell Line, Tumor, Estrogen Receptor alpha, E2F Transcription Factors, Cyclin-Dependent Kinase 4, Mice
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