SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Wang, Yuanzhong; Zhou, Dujin; Phung, Sheryl; Warden, Charles; Rashid, Rumana; Chan, Nymph; Chen, Shiuan

doi:10.1073/pnas.1612991114

Cited by 28 publications

(28 citation statements)

References 52 publications

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“…In support of our view, other studies have demonstrated that activated GR preferentially suppresses the function of AP-1 family members (39,40). In addition, synergistic upregulation of SGK1 expression by E 2 and dexamethasone facilitates maintenance of the homeostasis in the endoplasmic reticulum to antiapoptosis (41,42). All of these findings suggest that activated GR is a potent regulator of multiple stress-responsive transcription factors, thereby modulating stress and inflammatory responses.…”

Section: Discussionsupporting

confidence: 86%

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Fan

Siwak

Abderrahman

et al. 2019

Molecular Cancer Therapeutics

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Our clinically relevant finding is that glucocorticoids block estrogen (E 2)-induced apoptosis in long-term E 2-deprived (LTED) breast cancer cells. However, the mechanism remains unclear. Here, we demonstrated that E 2 widely activated adipose inflammatory factors such as fatty acid desaturase 1 (FADS1), IL6, and TNFa in LTED breast cancer cells. Activation of glucocorticoid receptor (GR) by the synthetic glucocorticoid dexamethasone upregulated FADS1 and IL6, but downregulated TNFa expression. Furthermore, dexamethasone was synergistic or additive with E 2 in upregulating FADS1 and IL6 expression, whereas it selectively and constantly suppressed TNFa expression induced by E 2 in LTED breast cancer cells. Regarding regulation of endoplasmic reticulum stress, dexamethasone effectively blocked activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) by E 2 , but it had no inhibitory effects on inositol-requiring protein 1 alpha (IRE1a) expression increased by E 2. Consistently, results from reverse-phase protein array (RPPA) analysis demonstrated that dexamethasone could not reverse IRE1a-mediated degradation of PI3K/Akt-associated signal pathways activated by E 2. Unexpectedly, activated GR preferentially repressed nuclear factor-kB (NF-kB) DNA-binding activity and expression of NF-kB-dependent gene TNFa induced by E 2 , leading to the blockade of E 2-induced apoptosis. Together, these data suggest that trans-suppression of NF-kB by GR in the nucleus is a fundamental mechanism thereby blocking E 2-induced apoptosis in LTED breast cancer cells. This study provided an important rationale for restricting the clinical use of glucocorticoids, which will undermine the beneficial effects of E 2-induced apoptosis in patients with aromatase inhibitorresistant breast cancer.

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Section: Discussionsupporting

confidence: 86%

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Fan

Siwak

Abderrahman

et al. 2019

Molecular Cancer Therapeutics

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“…Recently, a novel function of PERK was described 46 , 47 as a structural tether to increase the proximity of contact sites between the endoplasmic reticulum and mitochondria, which may facilitate oxidative stress. Nevertheless, how PERK actually modulates these stress-responsive transcription factors is various, which depends on the extent of PERK activation and different cell context 48 . All of these findings support the conclusion that PERK plays a central role to convey both adaptive and apoptotic signals from the endoplasmic reticulum to the nucleus 49 .…”

Section: Discussionmentioning

confidence: 99%

Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells

Fan

Tyagi

Agboke

et al. 2018

Cell Death Discovery

102

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Stress responses are critical for estrogen (E2)-induced apoptosis in E2-deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is an important therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2-deprived breast cancer cells is unknown. Here, we demonstrated that E2 differentially modulates NF-κB activity according to treatment time. E2 initially has significant potential to suppress NF-κB activation; it completely blocks tumor necrosis factor alpha (TNFα)-induced activation of NF-κB. We found that E2 preferentially and constantly enhances the expression of the adipogenic transcription factor CCAAT/enhancer binding protein beta (C/EBPβ), which is responsible for the suppression of NF-κB activation by E2 in MCF-7:5C cells. Interestingly, NF-κB p65 DNA-binding activity is increased when E2 is administered for 48 h, leading to the induction of TNFα and associated apoptosis. Blocking the nuclear translocation of NF-κB can completely prevent the induction of TNFα and apoptosis induced by E2. Further examination revealed that protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response (UPR), plays an essential role in the late activation of NF-κB by E2. This modulation between PERK and NF-κB is mainly mediated by a stress responsive transcription factor, transducer and activator of transcription 3 (STAT3), independently of the classic canonical IκBα signaling pathway. Thus, inhibition of PERK kinase activity completely blocks the DNA binding of both STAT3 and NF-κB, thereby preventing induction of NF-κB-dependent genes and E2-induced apoptosis. All of these findings suggest that PERK is a key regulator to convey stress signals from the endoplasmic reticulum to the nucleus and illustrate a crucial role for the novel PERK/STAT3/NF-κB/TNFα axis in E2-induced apoptosis in E2-deprived breast cancer cells.

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“…Although combining lapatinib and PI3K inhibitors could be limited by toxicity (71), targeting pathway rewiring could prove beneficial. SGK3 is an estrogen receptor target gene (72,73), but less is known about the role of ER-SGK3 axis in cancer. Comporting with previous reports that SGK1 or SGK3 can mediate AKT-independent activation of mTORC1 and survival in cancer cells treated with PI3K⍺-specific or AKT inhibitors (38,42), our data implicate SGK3 as a key ER target that mediates survival in response to HER2 inhibition in luminal-like DTPs.…”

Section: Discussionmentioning

confidence: 99%

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Chang

Jiang

Sayad

et al. 2020

Preprint

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Despite advances in targeted therapeutics, resistance remains a significant clinical problem in HER2-positive (HER2+) breast cancer and can lead to recurrence, metastasis, and death. “Drug-tolerant persisters” (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs following HER2 TKIs exposure have not been characterized extensively. We found that treatment of HER2+ breast cancer lines with lapatinib evoked DTPs with either a luminal-like or a mesenchymal-like transcriptional program and differential sensitivity to lapatinib/anti-estradiol combinations. Lentiviral barcoding and single cell RNA-sequencing showed that luminal-like HER2+ cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like signature, which uniquely gives rise to DTPs upon lapatinib exposure. Lapatinib-DTPs from luminal-like HER2+ cells survive via estrogen receptor-dependent induction of SGK3, thereby rewiring their PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. These results provide new insights into DTP ontogeny and therapeutic vulnerabilities.STATEMENT OF SIGNIFICANCEDTPs are implicated in resistance to TKIs, other targeted therapies, and some chemotherapies, but their ontogeny and vulnerabilities remain unclear. We find that lapatinib-DTPs engage either of two distinct transcriptional programs. At least one type of DTP arises selectively from cells transiting through a G0-like state and exhibits unique vulnerabilities compared with parental HER2+ breast cancer cells.

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SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Cited by 28 publications

References 52 publications

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells

Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

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