Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Núñez, Nomelí P.; Jelovac, Danijela; Macedo, Luciana F.; Berrigan, David; Perkins, Susan N.; Hursting, Stephen D.; Barrett, J. Carl; Brodie, Angela

doi:10.1158/1078-0432.ccr-04-0261

Cited by 19 publications

(10 citation statements)

References 31 publications

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“…Since the mouse uterus is extremely sensitive to estrogen stimulation, changes in uterine weight are useful in monitoring estrogen effects in vivo (16-18). As previously shown, AIs block estrogen production and reduce uterine weight (19-23). While ENT at 2.5mg/kg/day inhibited tumor growth, it had no effect on the estrogen sensitive mouse uterus (Figure-3B).…”

Section: Resultsmentioning

confidence: 73%

Functional Activation of the Estrogen Receptor-α and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole

et al. 2011

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Approximately 25% of breast cancers do not express the estrogen receptor-a (ERa) and consequently do not respond to endocrine therapy. In these tumors, ERa repression is often due to epigenetic modifications such as methylation and histone deacetylation. For this reason, we investigated the ability of the histone deacetylase inhibitor entinostat (ENT) to trigger reexpression of ERa and aromatase in breast cancer cells, with the notion that this treatment would restore sensitivity to the aromatase inhibitor (AI) letrozole. ENT treatment of tumor cells increased expression of ERa and aromatase, along with the enzymatic activity of aromatase, in a dosedependent manner both in vitro and in vivo. Notably, ERa and aromatase upregulation resulted in sensitization of breast cancer cells to estrogen and letrozole. Tumor growth rate was significantly lower in tumor xenografts following treatment with ENT alone and in combination with letrozole than in control tumors (P > 0.001). ENT plus letrozole also prevented lung colonization and growth of tumor cells, with a significant reduction (P > 0.03) in both visible and microscopic foci. Our results show that ENT treatment can be used to restore the letrozole responsiveness of ER-negative tumors. More generally, they provide a strong rationale for immediate clinical evaluation of combinations of histone deacetylase and aromatase inhibitors to treat ER-negative and endocrineresistant breast cancers. Cancer Res; 71(5); 1893-903. Ó2011 AACR.

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Section: Resultsmentioning

confidence: 73%

Functional Activation of the Estrogen Receptor-α and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole

et al. 2011

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“…The ability of the glyceollin mixture to function as an estrogen antagonist in the uteri in mice is a distinct advantage when compared with other phytoestrogens and tamoxifen. In several studies, tamoxifen has increased uterine weight and acts as an agonist in the uteri (3,29,30). These results suggest that the glyceollin mixture may be functioning as phyto -selective estrogen receptor modulators, selectively antagonizing ER function in a tissue type -specific manner.…”

Section: Discussionmentioning

confidence: 91%

Antiestrogenic Glyceollins Suppress Human Breast and Ovarian Carcinoma Tumorigenesis

Salvo

Boué

Fonseca

et al. 2006

Clinical Cancer Research

111

131

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Purpose: We have identified the phytoalexin compounds glyceollins I, II, and III, which exhibit marked antiestrogenic effects on estrogen receptor function and estrogen-dependent tumor growth in vivo. The purpose of this study was to investigate the interactions among the induced soy phytoalexins glyceollins I, II, and III on the growth of estrogen-dependent MCF-7 breast cancer and BG-1ovarian cancer cells implanted in ovariectomized athymic mice. Experimental Design: Four treatment groups for each cell line were used: vehicle control, 20 mg/kg/mouse/d glyceollin mixture injection, 0.72 mg estradiol (E2) implant, and E2 implant + 20 mg/kg/mouse/d glyceollin injection. Results: Treatment with glyceollin suppressed E2-stimulated tumor growth of MCF-7 cells (À53.4%) and BG-1 cells (À73.1%) in ovariectomized athymic mice. These tumor-inhibiting effects corresponded with significantly lower E2-induced progesterone receptor expression in the tumors. In contrast to tamoxifen, the glyceollins had no estrogen-agonist effects on uterine morphology and partially antagonized the uterotropic effects of estrogen. Conclusions: These findings identify glyceollins as antiestrogenic agents that may be useful in the prevention or treatment of breast and ovarian carcinoma.

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“…This is biologically plausible because many of these growth factors can promote mammary tumor growth and breast cancer tumor metastases (5,15,17,18). In addition, CR, which prevents obesity and protects against mammary cancer in multiple models, is associated with a reduction of many of these growth factors and adipokines (10,11,(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Obesity Accelerates Mouse Mammary Tumor Growth in the Absence of Ovarian Hormones

Núñez

Perkins

Smith

et al. 2008

Nutrition and Cancer

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Obesity increases incidence and mortality of breast cancer in postmenopausal women. Mechanisms underlying this association are poorly understood. Suitable animal models are needed to elucidate potential mechanisms for this association. To determine the effects of obesity on mammary tumor growth, nonovariectomized and ovariectomized C57BL/6 mice of various body weights (lean, overweight, and obese) were implanted subcutaneously with mammary tumor cells from syngeneic Wnt-1 transgenic mice. In mice, the lean phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status. Ovariectomy delayed Wnt-1 tumor growth consistent with the known hormone responsiveness of these tumors. However, obesity accelerated tumor growth in ovariectomized but not in nonovariectomized animals. Diet-induced obesity in a syngeneic mouse model of breast cancer enhanced tumor growth, specifically in the absence of ovarian hormones. These results support epidemiological evidence that obesity is associated with increased breast cancer incidence and mortality in postmenopausal but not premenopausal women. In contrast, maintaining a lean body weight phenotype was associated with reduced Wnt-1 tumor growth regardless of ovarian hormone status.

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Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Cited by 19 publications

References 31 publications

Functional Activation of the Estrogen Receptor-α and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole

Functional Activation of the Estrogen Receptor-α and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole

Antiestrogenic Glyceollins Suppress Human Breast and Ovarian Carcinoma Tumorigenesis

Obesity Accelerates Mouse Mammary Tumor Growth in the Absence of Ovarian Hormones

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