ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization

Wrobel, Kinga; Zhao, Yijia; Kulkoyluoglu, Eylem; Chen, Karen Lee Ann; Hieronymi, Kadriye; Holloway, Jamie N.; Li, Sarah; Ray, Tania; Ray, Partha S.; Landesman, Yosef; Lipka, Alexander E.; Smith, Rebecca; Madak-Erdoğan, Zeynep

doi:10.1210/me.2016-1101

Cited by 18 publications

(42 citation statements)

References 71 publications

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“…For cell proliferation experiments, cells were seeded at 500 cells/well in triplicate (unless otherwise stated) in 96-well plates (19). The cells were treated with vehicle (0.1% ethanol) or indicated doses of ligands and inhibitors at the concentrations indicated on the 2nd and 5th day.…”

Section: Cell Proliferation Migration and Mtor Pathway Activation Amentioning

confidence: 99%

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

et al. 2019

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Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERa)-positive (ER þ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERa signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER þ breast cancer cells. FFAs activated both the ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERa and mTOR sig-naling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER þ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERa and mTOR signaling cross-talk would be tested to prevent ER þ breast cancers in obese postmenopausal women. Significance: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

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Section: Cell Proliferation Migration and Mtor Pathway Activation Amentioning

confidence: 99%

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

et al. 2019

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“…Growth inhibition, apoptosis Mechanism related to STAT3 and survivin [162] In vitro /xenograft Selinexor Restores sensitivity to tamoxifen [163] In vitro /xenograft Selinexor…”

Section: Kpt-251 Kpt-276mentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…Tamoxifen, a selective estrogen receptor modulator (SERM), is one of the most effective endocrine therapy for estrogen receptor (ER)-positive breast cancer (2). However, approximately 30-40% of ER-positive breast cancer patients do not respond to tamoxifen endocrine therapy, and moreover, tumors that initially respond to tamoxifen treatment develop resistance to this drug over time (3,4). The mechanisms underlying tamoxifen resistance are complex and remain unclear, although loss of ER expression or dysregulation of ER co-regulators, and activation of many kinases such as the receptor tyrosine kinase have been found to contribute to tamoxifen resistance (5).…”

Section: Introductionmentioning

confidence: 99%

EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

et al. 2017

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Enhancer of zeste homologue 2 (EZH2), a catalytic subunit of polycomb repressive complex 2, is overexpressed in a number of different tumors including breast cancer, and serves important roles in cell cycle regulation, proliferation, apoptosis, tumorigenesis and drug resistance. However, it remains unclear whether EZH2 contributes to tamoxifen resistance in breast cancer. In the present study, the role of EZH2 in tamoxifen resistance in MCF‑7 cells was investigated. EZH2 was overexpressed in MCF‑7 tamoxifen‑resistant (MCF‑7 TamR) cells. EZH2 overexpression decreased the sensitivity of MCF‑7 cells to tamoxifen, and EZH2 knockdown improved the sensitivity of MCF‑7 TamR cells to tamoxifen. Furthermore, EZH2 knockdown induced cell cycle arrest in MCF‑7 TamR cells, accompanied by a decrease in cyclin D1 expression and an increase in p16 expression. EZH2 knockdown reduced p16 gene methylation in MCF‑7 TamR cells. These findings suggested that EZH2 overexpression may contribute to tamoxifen resistance in breast cancer, and EZH2 inhibition may reverse tamoxifen resistance in breast cancer by regulating the cell cycle via the demethylation of the p16 gene. Thus, EZH2 inhibitors may be effective for treating tamoxifen resistance in breast cancer.

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ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization

Cited by 18 publications

References 71 publications

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

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