Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer
Chellappagounder Thangavel1, Jeffry L Dean, Adam Ertel
1Kimmel Cancer Center, Philadelphia, Pennsylvania 19107, USA.
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.
Insights
Acquired resistance to endocrine therapy is a challenge in ER-positive breast cancer. Targeting cell cycle regulators like cyclin D1 and RB may offer new therapeutic options for hormone-refractory tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Endocrine therapy is a primary treatment for estrogen receptor (ER)-positive breast cancer.
- Acquired resistance to endocrine therapy presents a significant clinical challenge.
- Understanding resistance mechanisms is crucial for developing alternative therapeutic strategies.
Purpose of the Study:
- To identify common therapeutic targets in ER-positive breast cancer models resistant to endocrine therapy.
- To investigate the role of cell cycle progression and RB/E2F pathway in endocrine resistance.
- To evaluate the efficacy of targeting cell cycle kinases in hormone-refractory breast cancer.
Main Methods:
- Utilized model systems of ER-positive breast cancer with varying endocrine therapy sensitivity.
- Analyzed cell cycle progression markers, including cyclin D1 expression and RB phosphorylation.
- Assessed the impact of CDK4/6 inhibition (PD-0332991) on hormone-refractory models.
Main Results:
- Cell cycle progression was uncoupled from ER activity in resistant models.
- Cyclin D1 expression and RB phosphorylation persisted despite ER ablation.
- RB/E2F transcriptional control was deregulated in therapy-resistant cells.
- A gene expression signature of RB-dysfunction correlated with poor endocrine response in luminal B breast cancer.
- PD-0332991 effectively suppressed proliferation and induced cell cycle arrest and senescence in hormone-refractory models.
Conclusions:
- Suppression of cyclin D-dependent kinase activity and restoration of RB function are potential therapeutic strategies for endocrine-resistant breast cancer.
- CDK4/6 inhibition offers a viable approach for treating tumors that have failed endocrine therapy.
- Downstream cytostatic therapies, like CDK4/6 inhibitors, demonstrate clinical utility in overcoming endocrine resistance.
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