Therapeutically activating RB

Reestablishing cell cycle control in endocrine therapy-resistant breast cancer

Chellappagounder Thangavel, Jeffry L. Dean, Adam Ertel, Karen E. Knudsen, C. Marcelo Aldaz, Agnieszka K. Witkiewicz, Robert Clarke, Erik S. Knudsen

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER is a major clinical challenge. Here, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. In this context, cyclin D1 expression and retinoblastoma tumor suppressor protein (RB) phosphorylation are maintained even with efficient ablation of ER with pure antagonists. These therapy-resistant models recapitulate a key feature of deregulated RB/E2F transcriptional control. Correspondingly, a gene expression signature of RB-dysfunction is associated with luminal B breast cancer, which exhibits a relatively poor response to endocrine therapy. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed. Importantly, PD-0332991 led to a stable cell cycle arrest that was fundamentally distinct from those elicited by ER antagonists, and was capable of inducing aspects of cellular senescence in hormone therapy refractory cell populations. These findings underscore the clinical utility of downstream cytostatic therapies in treating tumors that have experienced failure of endocrine therapy.

Original languageEnglish (US)
Pages (from-to)333-345
Number of pages13
JournalEndocrine-Related Cancer
Volume18
Issue number3
DOIs
StatePublished - Jun 2011

Fingerprint

Cell Cycle Checkpoints
Breast Neoplasms
Estrogen Receptors
Therapeutics
Hormones
Cyclin D
Tumor Suppressor Proteins
Retinoblastoma Protein
Cell Aging
Cyclin D1
Cytostatic Agents
Cell- and Tissue-Based Therapy
Transcriptome
Neoplasms
Cell Cycle
Phosphotransferases
Phosphorylation

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Therapeutically activating RB : Reestablishing cell cycle control in endocrine therapy-resistant breast cancer. / Thangavel, Chellappagounder; Dean, Jeffry L.; Ertel, Adam; Knudsen, Karen E.; Aldaz, C. Marcelo; Witkiewicz, Agnieszka K.; Clarke, Robert; Knudsen, Erik S.

In: Endocrine-Related Cancer, Vol. 18, No. 3, 06.2011, p. 333-345.

Research output: Contribution to journalArticle

Thangavel, C, Dean, JL, Ertel, A, Knudsen, KE, Aldaz, CM, Witkiewicz, AK, Clarke, R & Knudsen, ES 2011, 'Therapeutically activating RB: Reestablishing cell cycle control in endocrine therapy-resistant breast cancer', Endocrine-Related Cancer, vol. 18, no. 3, pp. 333-345. https://doi.org/10.1530/ERC-10-0262
Thangavel, Chellappagounder ; Dean, Jeffry L. ; Ertel, Adam ; Knudsen, Karen E. ; Aldaz, C. Marcelo ; Witkiewicz, Agnieszka K. ; Clarke, Robert ; Knudsen, Erik S. / Therapeutically activating RB : Reestablishing cell cycle control in endocrine therapy-resistant breast cancer. In: Endocrine-Related Cancer. 2011 ; Vol. 18, No. 3. pp. 333-345.
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