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Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

ABSTRACT: Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival but comes with side effects that impact health and quality of life. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating several aspects of the human response. Single cell RNA sequencing reveals that tamoxifen induces widespread gene expression changes in the hypothalamus, particularly in neurons and ependymal cells. These effects are largely dependent on estrogen receptor alpha (ERα), as conditional ERα knockout ablated or reversed tamoxifen-induced changes in gene expression, thermoregulation, bone, and movement. These findings provide mechanistic insights into the effects of tamoxifen on the hypothalamus and suggest that hypothalamic ERα mediates several side effects of tamoxifen therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE158960 | GEO | 2021/02/01

REPOSITORIES: GEO

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Project description:Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using human phosphokinase array to profile kinase signaling pathways, we found that 4-OH Tamoxifen, SXR or their combination induced differential Akt phosphorylation profiles, changing the phosphorylation status and activity of the kinase. Also, our RNA sequencing data indicated that 4-OH Tamoxifen+SXR combination treatment causes gene expression changes distinct from 4-OH Tamoxifen and SXR treatments alone in tamoxifen-resistant cell lines. Since we observed dramatic changes in Akt activity and we saw a differential gene expression pattern with individual and combined 4-OH Tamoxifen and SXR treatments, we hypothesized that metabolic profile of breast cancer cells would change in the presence of 4-OH Tamoxifen and SXR. Using Seahorse metabolic profiler and cell viability experiments in limited media conditions, we showed that tamoxifen resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodelling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role of ERα-XPO1 crosstalk plays in reducing cancer recurrences.

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Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

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