Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers

Abstract

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

Targeting metabolic adaptations in the breast cancer–liver metastatic niche using dietary approaches to improve endocrine therapy efficacy

“…The copyright holder for this preprint this version posted September 7, 2021. ; https://doi.org/10.1101/2021.09.07.458711 doi: bioRxiv preprint to deformation, as well as response of cancer cells grown in these matrices to drugs [19,54]. We found that, consistent with the clinical observation, MBC cells grown on liver hydrogels were less responsive to Fulv compared to cells grown on Matrigel or lung or bone hydrogels.…”

“…1B). To characterize ER antagonist responses of MBC cells and test potential efficacy of combination therapies, we previously used decellularized hydrogels from different metastatic tissues [19]. To examine the differences in Fulv response when MBC cells are grown in different hydrogels, we used MCF7-ESR1 Y537S cells (Fig.…”

“…Then, these plates were incubated at 37ºC in a humidified environment with 5% CO 2 for at least for 1 hour. MCF7-ESR1 Y537S cells were seeded on coated plates after removing native coat mixtures at a density of (Sigma) for 24 h. Concentrations of drugs were selected are based on our previously published studies [19,24] and clinical data [25][26][27]. Experiments were performed in triplicate.…”

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

“…ERα has been shown to interact with the peroxisome proliferator-activated receptor gamma coactivator 1-alpha ( PPARGC1A) , a transcriptional coactivator for many steroid hormone receptor and nuclear receptors, to allow Luminal B subtype HR+ breast cancer brain metastatic cells to grow independent of glucose. In doing so, these tumors become dependent on amino acid metabolism and this shift in metabolic state has been associated with poor prognosis [ 137 ]. Further studies have demonstrated that PGC1α can also interact with ERRα to maintain metabolic plasticity by promoting specific gene expression programs.…”

“…Consistent with these findings, activation of PGC1α/ERRα signaling results in increased glutamine dependency and therapeutic resistance in metastatic breast cancer and circulating cancer cells. Several studies have demonstrated that PGC1α regulates the expression of a necessary gene expression programs, including expression of nuclear export protein exportin 1 (XPO1), that enables tumor cells to maintain metabolic plasticity, increase glutamine dependency, maintain cell growth and sustain invasiveness under limited nutrition conditions [ 137 , 138 , 139 , 140 , 141 , 142 ]. A number of additional studies have reported that ERRα can promote lapatinib resistance in breast cancer cells through increasing glutamine flux [ 224 ].…”