Cited by 346Estrogen and related hormone effectsAdvanced Breast Cancer TherapiesBreast Cancer Treatment Studies

ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer

Open access
Miller, Todd W., Balko, Justin M., Fox, Emily M., Ghazoui, Zara, Dunbier, Anita, Anderson, Helen, Dowsett, Mitch, Jiang, Aixiang +11 more·2011·Cancer Discovery

Published version of a preprint

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

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/2159-8290.cd-11-0101

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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.
Venue
Cancer Discovery
Published
2011-09-01
Volume
1
Issue
4
Pages
338-351
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review