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Regulatory Crosstalk of Doxorubicin, Estradiol and TNF? Combined Treatment in Breast Cancer-derived Cell Lines.

ABSTRACT: We present a new model of ESR1 network regulation based on analysis of Doxorubicin, Estradiol, and TNF? combination treatment in MCF-7. We used Doxorubicin as a therapeutic agent, TNF? as marker and mediator of an inflammatory microenvironment and 17?-Estradiol (E2) as an agonist of Estrogen Receptors, known predisposing factor for hormone-driven breast cancer, whose pharmacological inhibition reduces the risk of breast cancer recurrence. Based on the results of transcriptomics analysis, we found 71 differentially expressed genes that are specific for the combination treatment with Doxorubicin?+?Estradiol?+?TNF? in comparison with single or double treatments. The responsiveness to the triple treatment was examined for seven genes by qPCR, of which six were validated, and then extended to four additional cell lines differing for p53 and/or ER status. The results of differential regulation enrichment analysis highlight the role of the ESR1 network that included 36 of 71 specific differentially expressed genes. We propose that the combined activation of p53 and NF-kB transcription factors significantly influences ligand-dependent, ER-driven transcriptional responses, also of the ESR1 gene itself. These results provide a model of coordinated interaction of TFs to explain the Doxorubicin, E2 and TNF? induced repression mechanisms.

SUBMITTER: Nassiri I

PROVIDER: S-EPMC6811586 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Regulatory Crosstalk of Doxorubicin, Estradiol and TNFα Combined Treatment in Breast Cancer-derived Cell Lines.

Nassiri Isar I Inga Alberto A Meškytė Erna Marija EM Alessandrini Federica F Ciribilli Yari Y Priami Corrado C

Scientific reports 20191023 1

We present a new model of ESR1 network regulation based on analysis of Doxorubicin, Estradiol, and TNFα combination treatment in MCF-7. We used Doxorubicin as a therapeutic agent, TNFα as marker and mediator of an inflammatory microenvironment and 17β-Estradiol (E2) as an agonist of Estrogen Receptors, known predisposing factor for hormone-driven breast cancer, whose pharmacological inhibition reduces the risk of breast cancer recurrence. Based on the results of transcriptomics analysis, we foun ...[more]

PMID: 31645610

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Project description:Chemoresistance is the major cause of cancer recurrence, relapse and eventual death. Doxorubicin resistance is one such challenge in breast cancer. The use of quercetin, an antioxidant, in combination with doxorubicin has been investigated for offering protection to normal cells from the toxic side effects of doxorubicin in addition to modulation of its resistance. The present study aimed to investigate the effects of quercetin in prevention of a doxorubicin-chemoresistant phenotype in both doxorubicin-sensitive and -resistant human MCF-7 breast cancer cell lines. A doxorubicin-resistant MCF-7 cell line was established. The development of resistant cells was closely monitored for changes in morphological features. Sensitivity to doxorubicin and the doxorubicin/quercetin combination was assessed using the tetrazolium assay. To determine the mechanism by which quercetin sensitizes the doxorubicin MCF-7-resistant cell line to doxorubicin, gene expression alterations in breast cancer-related genes were examined using the reverse transcription-quantitative PCR (RT-qPCR) array technology. Resistant MCF cells were successfully developed and the inhibitory concentration (IC50) value of doxorubicin increased from 0.133 to 4 µM (wild-type to resistant). The effects of the quercetin/doxorubicin combination exhibited different effects on wild-type vs. resistant cells. The IC50 of doxorubicin was reduced in wild cells, whereas resistant cells showed an increase in cell viability at lower concentrations and a potentiation of the effects of doxorubicin only at higher concentrations. Annexin V/propidium iodide staining demonstrated that quercetin drives cells into late apoptosis and necrosis, but in resistant cells, necrosis predominates. RT-qPCR results revealed that quercetin led to a reversal in doxorubicin effects via up- and downregulation of important genes such as SNAI2, PLAU and CSF1 genes. Downregulation of cell migration genes, SNAI2 (-31.23-fold) and plasminogen activator, urokinase (PLAU; -30.62-fold), and the apoptotic pathway gene, colony stimulating factor 1 (CSF1; -17.25-fold) were the most important querticin-associated events. Other gene alterations were also observed involving cell cycle arrest and DNA repair pathways. The results of the present study indicated that quercetin could lead to a reversal of doxorubicin resistance in breast cancer cells via downregulation of the expression of important genes, such as SNAI2, PLAU and CSF1. Such findings may represent a potential strategy for reversing breast cancer cell-related chemoresistance.

Project description:The aims of this study were to compare 12-week outcomes of single-therapy tolterodine (Detrol LA) extended release to intravaginal estrogen (Estrace) for overactive bladder (OAB) symptoms and characterize 24- and 52-week outcomes in women undergoing combined therapy.A single-site randomized, open-label trial in women with urinary frequency, urgency, nocturia, and/or urgency urinary incontinence symptoms was performed. Fifty-eight participants were randomized to oral tolterodine extended release daily or intravaginal estradiol cream nightly for 6 weeks then twice per week. The primary outcome was change in Overactive Bladder Questionnaire (OAB-q) symptom bother score at 12 weeks. Secondary outcomes included the Health-Related Quality of Life Questionnaire (HRQL) of the OAB-q and a 3-day bladder diary. At 12 weeks, subjects were offered addition of the alternative therapy with follow-up at 24 and 52 weeks.There was no difference in symptom bother score improvement between the tolterodine and intravaginal estradiol groups baseline to 12 weeks (20.6 ± 21.7, -15.8 ± 23.3, respectively, P = 0.45). There was a significant within-group decrease in symptom bother score from baseline to 12 weeks (tolterodine, P < 0.0001, and intravaginal estradiol, P = 0.002). Secondary outcome improvement within groups was noted in the HRQL total, urinary incontinence episodes, and median voiding frequency (all P ? 0.03) in the tolterodine group and in the HRQL total score (P = 0.03) in the intravaginal estradiol group, with no differences between groups. Combined therapy outcomes at 24 and 52 weeks compared with single therapy at 12 weeks revealed significant improvement in symptom bother score in the intravaginal estradiol + tolterodine group at 24 and 52 weeks (20.0 ± 23.9, P = 0.008; -16.7 ± 23.3, P = 0.02, respectively).Significant within-group improvement in OAB-q symptom bother was noted in both the intravaginal estradiol and tolterodine groups for OAB symptoms, with no difference between groups. Greater improvement from 12-week single therapy to 24 and 52 weeks of combined therapy was noted in the group originally assigned to intravaginal estradiol. The role of combined medical therapy for OAB symptoms needs further investigation.

Dataset Information

Regulatory Crosstalk of Doxorubicin, Estradiol and TNF? Combined Treatment in Breast Cancer-derived Cell Lines.

Publications

Regulatory Crosstalk of Doxorubicin, Estradiol and TNFα Combined Treatment in Breast Cancer-derived Cell Lines.

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