Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer

Adurthi, Sreenivas; Kumar, Manoj; Vinodkumar, H. S.; Mukherjee, Geetashree; Krishnamurthy, Hanumanthappa; Acharya, Kshitish K.; Bafna, U. D.; Uma, Devi K.; Abhishekh, B; Krishna, Sudhir; Parchure, Adwait Anand; Alka, Murali; Jayshree, R. S.

doi:10.1038/s41598-017-17102-w

Cited by 53 publications

(60 citation statements)

References 73 publications

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“…in the population of Tregs. Of interest, the estrogen signalling pathway was robustly upregulated in these cells consistent with previous data demonstrating that ER-alpha binds the FOXP3 gene promoter driving Tregs expansion and anti-inflammatory function [45,139]. As previously stated (see Section 6.1), we and others have highlighted a cross-talk between LRH-1/NR5A2 and ER-alpha that intimately cooperate to activate common target genes suggesting a role of LRH-1/NR5A2 in promoting the expansion of the Tregs population through a potential interaction with the FOXP3 gene promoter [94][95][96].…”

Section: The Anti-diabetic Benefits Of the Bl001/lrh-1/nr5a2 Signallisupporting

confidence: 87%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease that targets the destruction of islet beta-cells resulting in insulin deficiency, hyperglycemia and death if untreated. Despite advances in medical devices and longer-acting insulin, there is still no robust therapy to substitute and protect beta-cells that are lost in T1DM. Attempts to refrain from the autoimmune attack have failed to achieve glycemic control in patients highlighting the necessity for a paradigm shift in T1DM treatment. Paradoxically, beta-cells are present in T1DM patients indicating a disturbed equilibrium between the immune attack and beta-cell regeneration reminiscent of unresolved wound healing that under normal circumstances progression towards an anti-inflammatory milieu promotes regeneration. Thus, the ultimate T1DM therapy should concomitantly restore immune self-tolerance and replenish the beta-cell mass similar to wound healing. Recently the agonistic activation of the nuclear receptor LRH-1/ NR5A2 was shown to induce immune self-tolerance, increase beta-cell survival and promote regeneration through a mechanism of alpha-to-beta cell phenotypic switch. This trans-regeneration process appears to be facilitated by a pancreatic anti-inflammatory environment induced by LRH-1/NR5A2 activation. Herein, we review the literature on the role of LRH1/NR5A2 in immunity and islet physiology and propose that a cross-talk between these cellular compartments is mandatory to achieve therapeutic benefits.

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Section: The Anti-diabetic Benefits Of the Bl001/lrh-1/nr5a2 Signallisupporting

confidence: 87%

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Cobo-Vuilleumier

Gauthier

2020

Metabolism

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“…In cervical cancer, FOXP3 levels were reduced and suppressive function of Tregs was minimized in the presence of an ERα antagonist. These studies also found a complex of ERα, E2 and FOXP3 as well as ERα occupancy at the FOXP3 promoter (152). These data suggest that estrogenic signaling directly regulates Treg suppressive function through FOXP3.…”

Section: Estrogen Regulates Pro-tumor Infiltrating Lymphocytesmentioning

confidence: 60%

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.

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“…Estradiol is the most important steroid hormone in the normal female endocrine system (44); the present study identified that endogenous estradiol levels in patients with cervical cancer were higher compared with controls, which suggests that high endogenous estradiol levels are associated with an elevated risk of cervical cancer. Estrogen receptor-α binds to the forkhead box P3 promoter and modulates regulatory T-cell function in human cervical cancer (45). Therefore, sex hormones may have an influence on the immune system.…”

Section: Discussionmentioning

confidence: 99%

Association of estradiol and HPV/HPV16 infection with the occurrence of cervical squamous cell carcinoma

et al. 2019

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The associations between human papillomavirus (HPV) infection or hormonal exposure and cervical cancer risk are well established. However, to the best of our knowledge, the association between high endogenous estradiol levels in conjunction with HPV/HPV16 infection and the risk of cervical squamous cell carcinoma remains unknown. To investigate this, the current study conducted a matched case-control study in Shanxi Province, China, in which clinical samples were obtained from 74 females with newly diagnosed uterine cervix squamous cell carcinoma and 74 matched healthy females who were selected from 582 healthy females according to age, place of residence, marital status and menopausal status. From all participants, DNA was extracted from cells obtained from a cervical smear and serum was separated from venous blood withdrawn during days 5-8 of the menstrual cycle. HPV/HPV16 DNA and estradiol expression levels in the serum were measured by general polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Significant differences were identified in the positive HPV and HPV16 DNA expression rates between patients and controls, with odds ratios (95% confidence interval) of 3.74 (1.84-7.59) and 4.04 (1.97-8.28), respectively. Expression levels of estradiol in patients were significantly higher compared with the controls (P<0.001), however, this was only identified when the HPV16 E2 or E6 oncogene status was negative. Considering 40 ng/ml as the cutoff estradiol level, 78.38% of patients exhibited high estradiol levels, which was significantly higher than the percentage of controls (P<0.001). An additive interaction pattern was revealed between estradiol expression levels and HPV/HPV16 infection. The results suggest that among the various types of HPV, HPV16 may be most likely to cause uterine cervix squamous cell carcinoma and an abnormally high level of endogenous estradiol may further increase this risk. Therefore, estradiol therapy may represent a new treatment strategy for cases of cervical cancer associated with HPV infection.

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Oestrogen Receptor-α binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer

Cited by 53 publications

References 73 publications

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Time for a paradigm shift in treating type 1 diabetes mellitus: coupling inflammation to islet regeneration

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

Association of estradiol and HPV/HPV16 infection with the occurrence of cervical squamous cell carcinoma

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