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Delineating the molecular mechanisms of tamoxifen's oncolytic actions in estrogen receptor-negative cancers
1Department of Biology, College of Arts and Sciences, University of Rochester, Rochester, NY 14627, USA.
Abstract:
Since its clinical inception, tamoxifen (TAM) has proved to be a powerful tool in treating estrogen receptor-positive breast cancers while exhibiting manageable side effects. Although TAM was synthesized as an estrogen receptor antagonist, reports have found that a significant fraction of women with estrogen receptor-negative cancers have benefitted from TAM treatment, suggesting the possibility of an alternate anti-cancer mechanism. In this paper, we present a review of recent and past literature in an attempt to clarify how TAM inhibits cell proliferation and induces apoptosis in cells lacking the estrogen receptor. Our analysis indicates that micromolar concentrations of TAM selectively elevate intracellular calcium concentrations in malignant cells, possibly by inversely agonizing cannabinoid receptors, producing considerable mitochondrial distress followed by the rapid production of reactive oxygen species. In response, cytoplasmic proteins such as JNK1 are activated, which mediates the activation of caspase-8. Fyn kinase auto phosphorylates in response to increased reactive oxygen species and directs the ubiquitin ligase c-Cbl to tag growth factor receptors for ubiquitination, potentially abrogating constitutively active survival pathways that are hallmarks of cancer progression. We attempt to differentiate the effect that TAM has on purified Protein Kinase C (PKC) compared to that in an intact cell, suggesting that low micromolar concentrations of TAM indirectly inhibit PKC by inducing EGFR destruction and high micromolar concentrations of TAM inhibits PKC through a direct binding mechanism.
Insights
Tamoxifen (TAM) shows anti-cancer effects beyond estrogen receptors. It triggers cell death in cancer cells by disrupting calcium levels, mitochondria, and survival pathways, offering new therapeutic insights.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tamoxifen (TAM) is a standard treatment for estrogen receptor-positive breast cancer.
- TAM's efficacy in estrogen receptor-negative cancers suggests alternative anti-cancer mechanisms.
- Understanding these mechanisms is crucial for expanding TAM's therapeutic applications.
Purpose of the Study:
- To review and clarify the non-estrogen receptor-mediated mechanisms of TAM in inhibiting cancer cell proliferation and inducing apoptosis.
- To elucidate the signaling pathways involved in TAM's anti-cancer effects in cells lacking estrogen receptors.
Main Methods:
- Literature review of recent and past studies on TAM's anti-cancer effects.
- Analysis of TAM's impact on intracellular calcium, cannabinoid receptors, and mitochondrial function.
- Investigation of TAM's effects on JNK1, caspase-8, Fyn kinase, c-Cbl, and growth factor receptor ubiquitination.
- Differentiation of TAM's effects on Protein Kinase C (PKC) in purified versus intact cells.
Main Results:
- Micromolar TAM concentrations elevate intracellular calcium in malignant cells, potentially via cannabinoid receptors.
- This leads to mitochondrial distress, reactive oxygen species (ROS) production, and activation of JNK1 and caspase-8.
- TAM also induces Fyn kinase auto-phosphorylation and directs c-Cbl to degrade growth factor receptors, inhibiting survival pathways.
- TAM exhibits dual inhibition of PKC: indirect via EGFR destruction at low micromolar concentrations and direct binding at high concentrations.
Conclusions:
- TAM possesses potent anti-cancer activities independent of estrogen receptor antagonism.
- The proposed mechanism involves calcium dysregulation, mitochondrial stress, ROS generation, and disruption of key signaling pathways.
- These findings highlight TAM's potential in treating a broader range of cancers and offer avenues for novel therapeutic strategies.
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