Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers

Tsai, Cheng-Fang; Cheng, Yuan; Lu, Dah‐Yuu; Wang, Shulin; Chang, Chen-Ni; Chang, Pei-Chun; Yeh, Wei-Lan

doi:10.1016/j.taap.2017.11.020

Cited by 34 publications

(18 citation statements)

References 60 publications

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“…E2 administration increases GJA1 protein expression and gap junction communication in human myometrial cells [39,40]. Furthermore it has been reported in other tissues that inhibition of ERα66 reduced, while its overexpression increased GJA1 expression [41,42]. Our study however, demonstrates for the first time the role of alternate ERα isoforms in GJA1 regulation in the human myometrial cell.…”

Section: Discussionsupporting

confidence: 50%

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy

et al. 2019

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BackgroundCirculating estrogen (E2) levels are high throughout pregnancy and increase towards term, however its local tissue specific actions vary across gestation. For example, myometrial E2 regulated uterotonic action is disabled until term, whereas it's proliferative function is maintained in the breast. We have identified gestationally regulated splicing events, mediated by hnRNPG and modulated by E2 that generate alternatively spliced estrogen receptor alpha (ERα) variants (ERΔ7 and ERα46) in the myometrium. These variants allow for differential, gestationally regulated, modulation of the uterotonic action of E2.MethodsHuman myometrium isolated from preterm and term non-laboring and laboring pregnant women were analyzed for ERα isoforms and splice factor levels. Lentiviral mediated shRNA knockdown of hnRNPG and overexpression of ERΔ7 were performed in human myometrial (hTERT-HM) cells. Functional 3D collagen contraction assays were executed.FindingsERΔ7 acts as a dominant negative repressor of the uterotonic action of ERα66 and ERα46 isoforms through the regulation of the myometrial gap junction protein GJA1. Elimination of hnRNPG inhibits the generation of ERΔ7 while overexpression of ERΔ7 inhibited GJA1 expression. Moreover in vivo human myometrial hnRNPG levels decline at term in an E2 dependent manner resulting in a withdrawal of ERΔ7 levels and its tocolytic action at term.InterpretationOur findings implicate the unique role of ERΔ7 as a modulator of myometrial quiescence and define the mechanism of ERΔ7 generation, through hormonally regulated splicing events.FundThis study was supported by NIH OPRU U01 supplement (HD047905), University of Pittsburgh and Wayne State University Perinatal Research Initiative (USA).

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Section: Discussionsupporting

confidence: 50%

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy

et al. 2019

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“…Enhanced Cx43-GJIC, leading to improved efficacy of tamoxifen and lapatinib.[112, 113, 115]TAT-Cx43 266-283 GliomaA cell-penetrating peptide based on Cx43 (amino acids 266–283). Inhibited cell migration and invasion.[118]PQ1BreastIncreased Cx43 and decreased Cx46 expression.[121]4-OH-tamoxifenBreastDecreased Cx43 expression and migration.[122]FulvestrantBreastDecreased Cx43 expression and migration.[122]GinsenosidePTCIncreased Cx31 expression, leading to decreased cell proliferation.[81] GJIC Gap junctional intercellular communication, PTC Papillary thyroid cancer…”

Section: Therapeutic Applications Of Connexins As Targetsmentioning

confidence: 99%

“…A recent study found that a substituted quinoline, PQ1, increased Cx43 levels at early stages of tumor formation and decreased Cx46 levels at late stages of tumor formation [121]. Inhibition of estrogen receptor by fulvestrant or 4-OH-tamoxifen reduced Cx43 levels and migration of ER-positive MCF-7 and BT474 breast cancer cells [122]. Ginsenoside (Rg1) induced the expression of Cx31, resulting in the decreased proliferation of papillary thyroid cancer cells [81] (Table 3).…”

Section: Therapeutic Applications Of Connexins As Targetsmentioning

confidence: 99%

Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application

Wang

2019

J Biomed Sci

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Connexin, a four-pass transmembrane protein, contributes to assembly of gap junctions among neighboring cells and thus facilitates gap junctional intercellular communication (GJIC). Traditionally, the roles of connexins were thought to mediate formation of hemichannels and GJIC assembly for transportation of ions and small molecules. Many studies have observed loss of GJIC, due to reduced expression or altered cytoplasmic localization of connexins, in primary tumor cells. Connexins are generally considered tumor-suppressive. However, recent studies of clinical samples suggested a different role of connexins in that expression levels and membrane localization of connexins, including Connexin 43 (Cx43, GJA1) and Connexin 26 (Cx26, GJB2), were found to be enhanced in metastatic lesions of cancer patients. Cx43- and Cx26-mediated GJIC was found to promote cancer cell migration and adhesion to the pulmonary endothelium. Regulatory circuits involved in the induction of connexins and their functional effects have also been reported in various types of cancer. Connexins expressed in stromal cells were correlated with metastasis and were implicated in regulating metastatic behaviors of cancer cells. Recent studies have revealed that connexins can contribute to cellular phenotypes via multiple ways, namely 1) GJIC, 2) C-terminal tail-mediated signaling, and 3) cell-cell adhesion during gap junction formation. Both expression levels and the subcellular localization could participate determining the functional roles of connexins in cancer. Compounds targeting connexins were thus tested as potential therapeutics intervening metastasis or chemoresistance. This review focuses on the recent findings in the correlation between the expression of connexins and patients’ prognosis, their roles in metastasis and chemoresistance, as well as the implications and concerns of using connexin-targeting drugs as anti-metastatic therapeutics. Overall, connexins may serve as biomarkers for cancer prognosis and as therapeutic targets for intervening metastasis and chemoresistance.

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“…In recent years, it has been discovered that also small, non-coding RNA (siRNAs or miRNAs) can diffuse through connexin-made channels (Esseltine and Laird, 2016 ). The relevance of connexins and their tightly regulated function is highlighted by their implication in pathological states of completely different character, such as cancer (Tsai et al, 2018 ), inflammation (Li et al, 2018 ), and neurodegenerative diseases (Belousov et al, 2018 ). For this reason, modulation of connexin hemichannels is becoming increasingly interesting for the treatment of several diseases including Alzheimer Disease (Yi et al, 2017 ), skin disorders, or X-linked Charcot Marie Tooth disease (Sáez and Leybaert, 2014 ; Carrer et al, 2017 ; Xu et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Cues to Opening Mechanisms From in Silico Electric Field Excitation of Cx26 Hemichannel and in Vitro Mutagenesis Studies in HeLa Transfectans

Zonta

Buratto

Crispino

et al. 2018

Front. Mol. Neurosci.

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Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction channels. Comparison of experimental data and molecular dynamics simulations suggests that the published structures represent neither fully-open nor closed configurations. To facilitate the search for alternative stable configurations, we developed a coarse grained (CG) molecular model of the hCx26 hemichannel and studied its responses to external electric fields. When challenged by a field of 0.06 V/nm, the hemichannel relaxed toward a novel configuration characterized by a widened pore and an increased bending of the second transmembrane helix (TM2) at the level of the conserved Pro87. A point mutation that inhibited such transition in our simulations impeded hemichannel opening in electrophysiology and dye uptake experiments conducted on HeLa tranfectants. These results suggest that the hCx26 hemichannel uses a global degree of freedom to transit between different configuration states, which may be shared among the whole connexin family.

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Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers

Cited by 34 publications

References 60 publications

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy

Emerging roles of gap junction proteins connexins in cancer metastasis, chemoresistance and clinical application

Cues to Opening Mechanisms From in Silico Electric Field Excitation of Cx26 Hemichannel and in Vitro Mutagenesis Studies in HeLa Transfectans

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