Agonistic activity of tamoxifen, a selective estrogen-receptor modulator (SERM), on arthritic ovariectomized mice

Silva, Luiz André Santos; Félix, Franciel Batista; Araújo, Jéssica Maria Dantas; Souza, Elindayane Vieira de; Camargo, Enilton A.; Grespan, Renata

doi:10.1590/1414-431x20176799

Cited by 8 publications

(9 citation statements)

References 20 publications

(24 reference statements)

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“…Whilst functional significance of estrogen-induced down-regulation of blood neutrophils is yet to be elucidated, the study highlights the potential of estrogenic compounds in modulating neutrophil biology in cancer patients. Tamoxifen, a widely used drug in ERα-positive breast cancer, is reported to function as a selective estrogen receptor agonist in neutrophils and hematopoietic progenitor cells [ 36 , 37 ]. There have been reports of tamoxifen-induced neutropenia in breast cancer patients [ 38 , 39 ], which may be caused by tamoxifen’s estrogenic activity in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice

Lim

Lin

2021

BMC Cancer

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Background Neutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue. Methods Female BALB/cAnNTac mice at 7–8 weeks old were mated and bilateral ovariectomy was performed 2 days post-partum. At 24 h after forced-weaning of pups to induce mammary involution, post-partum female mice were injected with either E2V, or vehicle control on alternative days for 2-weeks. On 48 h post-weaning, treated female mice were inoculated subcutaneously with 4 T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. Animals were euthanized on day 14 post-tumour inoculation for analysis. To evaluate the short-term effect of estrogen, post-partum females were treated with only one dose of E2V on day 12 post-tumour inoculation. Results Estrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no significant effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48 h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice. Conclusions Prolonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.

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Section: Discussionmentioning

confidence: 99%

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice

Lim

Lin

2021

BMC Cancer

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show abstract

“…Whilst functional signi cance of estrogen-induced down-regulation of blood neutrophils is yet to be elucidated, the study highlights the potential of estrogenic compounds in modulating neutrophil biology in cancer patients. Tamoxifen, a widely used drug in ERα-positive breast cancer, is reported to function as a selective estrogen receptor agonist in neutrophils and hematopoietic progenitor cells [36,37]. There have been reports of tamoxifen-induced neutropenia in breast cancer patients [38,39], which may be caused by tamoxifen's estrogenic activity in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Markedly Reduces Circulating Low-density Neutrophils and Enhances Pro-tumoral Gene Expression in Neutrophil of Tumour-bearing Mice

Lim

Lin

2021

Preprint

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Background: Neutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue. Methods: Female BALB/cAnNTac mice at 7-8 weeks old were mated and bilateral ovariectomy performed two days post-partum. At 24h post-weaning, mice were treated with either E2V, or vehicle control once every 2 days. On 48h post-weaning, mice were inoculated subcutaneously with 4T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. For 48h E2V treatment, mice were treated with one dose of E2V on day 12 post-tumour inoculation. Animals were euthanized on day 14 post-tumour inoculation for analysis.Results: Estrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice. Conclusions: Prolonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.

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“…Previous studies have shown that hormones such as progesterone [18,19] and estradiol [10,[20][21][22] produce anti-inflammatory effects in several models of arthritis [23], but their modulatory properties are still contradictory. Our present results show that ovariectomy increase the articular inflammation in zymosan-induced arthritis.…”

Section: Discussionmentioning

confidence: 99%

Estradiol replacement therapy regulates innate immune response in ovariectomized arthritic mice

Schneider

Kanashiro

Dutra

et al. 2019

International Immunopharmacology

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Neuroendocrine changes are essential factors contributing to the progression and development of rheumatoid arthritis. However, the role of estrogen in the innate immunity during arthritis development is still controversial. Here, we evaluated the effect of estrous cycle, ovariectomy, estradiol replacement therapy and treatment with estrogen receptor (ER)α and ERβ specific agonists on joint edema formation, neutrophil recruitment, and articular levels of cytokines/ chemokines in murine zymosan-induced arthritis. Our results showed that articular inflammation of proestus/estrus was similar to metaestus/diestrus animals indicating that the inflammatory response in acute arthritis is not affected by the estrous cycle. However, ovariectomy increased joint swelling, neutrophil migration, and TNF-α level. Treatment for six consecutive days with estradiol cypionate re-established the acute inflammation in ovariectomized arthritic mice to responses similar to those in SHAM-proestrus/estrus or naive mice. Moreover, treatment with propylpyrazoletriol and diarylpropionitrile, two ERα and ERβ selective agonists, respectively, inhibited both edema and neutrophil recruitment. Finally, the non-genomic properties of estradiol were analyzed with an acute treatment with β-estradiol-water soluble, which reduced the edema only. In the present study, estradiol replacement therapy improves the innate immune responses in ovariectomized arthritic mice by activating nuclear estrogen receptors. These results suggest that *

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Agonistic activity of tamoxifen, a selective estrogen-receptor modulator (SERM), on arthritic ovariectomized mice

Cited by 8 publications

References 20 publications

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice

Estrogen Markedly Reduces Circulating Low-density Neutrophils and Enhances Pro-tumoral Gene Expression in Neutrophil of Tumour-bearing Mice

Estradiol replacement therapy regulates innate immune response in ovariectomized arthritic mice

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