Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer

El-Shennawy, Lamiaa; Dubrovskyi, Oleksii; Kastrati, Irida; Danes, Jeanne M.; Zhang, Yiqun; Whiteley, Herbert E.; Creighton, Chad J.; Frasor, Jonna

doi:10.1158/0008-5472.can-17-1686

Cited by 36 publications

(27 citation statements)

References 49 publications

(68 reference statements)

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“…Further, we also found P65 phosphorylation was activated by gastrin stimulation in ER positive BC cell lines. The similar results were also described that NF-κB could work cooperatively with ER to inhibit the proliferation of ER positive BC cells [ 53 , 54 ]. Despite a considerable body of evidence supporting the role for the NF-κB pathway in aggressive ER + breast tumors, the precise mechanism also need to be further investigated.…”

Section: Discussionsupporting

confidence: 75%

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Meng

Wang

et al. 2018

BMC Cancer

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BackgroundGastrin is an important gastrointestinal hormone produced primarily by G-cells in the antrum of the stomach. It normally regulates gastric acid secretion and is implicated in a number of human disease states, but how its function affects breast cancer (BC) development is not documented. The current study investigated the suppressive effects of gastrin on BC and its underlying mechanisms.MethodsSerum levels of gastrin were measured by enzyme-linked immunosorbent assay (ELISA) and correlation between gastrin level and development of BC was analyzed by chi-square test. Inhibitory effects of gastrin on BC were investigated by CCK-8 assay and nude mice models. Expressions of CCKBR/ERK/P65 in BC patients were determined through immunohistochemistry (IHC) and Western blot. Survival analysis was performed using the log-rank test.ResultsThe results indicated that the serum level of gastrin in BC patients was lower compared with normal control. Cellular and molecular experiments indicated that reduction of gastrin is associated with inactivation of cholecystokinin B receptor (CCKBR)/ERK/P65 signaling in BC cells which is corresponding to molecular type of estrogen receptor (ER) positive BC. Furthermore, we found that low expression of gastrin/CCKBR/ERK /P65 was correlated to worse prognosis in BC patients. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. Moreover, combination treatment with gastrin and tamoxifen more efficiently inhibited ER+ BC than tamoxifen alone.ConclusionsWe concluded that low serum gastrin is related to increased risk of ER+ BC development. The results also established that CCKBR/ERK/P65 signaling function is generally tumor suppressive in ER+ BC, indicating therapies should focus on restoring, not inhibiting, CCKBR/ERK/P65 pathway activity.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4717-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 75%

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Meng

Wang

et al. 2018

BMC Cancer

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“…Importantly, the cytokine-induced gene program in MCF7 breast cancer cells can induce extravasation, an important part of the metastatic process, and this occurs through ER but independently of estradiol (Stender et al 2017). Consistently, overexpressing a constitutive active form of IKKβ, which is a key kinase downstream from TNFα, increases invasion in vitro and in vivo in the presence of estradiol (El-Shennawy et al 2018). Interestingly, MCF7 breast cancer cells also become resistant to tamoxifen in the presence of these cytokines, showing that extracellular stimuli, in the form of specific cytokines, can modulate drug responsiveness.…”

Section: Cytokinesmentioning

confidence: 91%

Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

2018

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Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.

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“…Estrogeninduced phosphorylation of ERα and its transcriptional activation through phosphorylation of ERα on Ser118 preferentially involves IκB kinase-α (IKK-α) (Park et al 2005, Weitsman et al 2006. However, IKKβ and IKKϵ regulate as well, ERα activity and the expression of its target genes (Guo et al 2016, El-Shennawy et al 2018. Interestingly, decreased phosphorylation of IκBα occurs after estrogen treatment of HeLa cells stably transfected with a cDNA encoding the human ERα (Sun et al 1998) or in rat brain (Wen et al 2004), suggesting that E2 directly regulates IKK activity.…”

Section: Figurementioning

confidence: 99%

Estrogen receptor α regulates the expression of syndecan-1 in human breast carcinoma cells

Fleurot

Goudin

Hanoux

et al. 2019

Endocrine-Related Cancer

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Breast cancer (BC) is the primary cause of cancer-related mortality among women. Patients who express the estrogen receptor (ER), which mediates the tumorigenic effects of estrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to E2 is associated with aggressive malignant phenotypes, which lead to relapse. These BC subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis as well as the proliferation and invasiveness of cancer cells. We showed here that the activation of ER-alpha (ERα) by estrogens induces downregulation of SDC1 expression in ER(+) MCF7 cells but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER downregulator, led to subsequent SDC1 overexpression. E2-dependent downregulation of SDC1 expression required de novo protein synthesis and was antagonized by treatment with BAY 11-7085, an irreversible inhibitor of IκBα phosphorylation, which inhibits the activation of NFκB. Downregulation of SDC1 expression required ERα and activation of IKK, but was independent to downstream transcriptional regulators of NFκB. BAY 11-7085 prevented E2-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilized E2-activated ERα, leading to subsequent downregulation of SDC1 expression. Our results showed that sustained ER signaling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER(+) BC as well as the overexpression of SDC1 in hormone receptor-negative BC subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for BC as well as for other endocrine-associated cancers.

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Coactivation of Estrogen Receptor and IKKβ Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer

Cited by 36 publications

References 49 publications

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling

Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

Estrogen receptor α regulates the expression of syndecan-1 in human breast carcinoma cells

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