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Preclinical and clinical development of new progesterone receptor antagonists with high receptor specificity for breast cancer treatment
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
J. Hoffmann, H. Hess-Stumpp, R. B. Lichtner, U. Fuhrmann, G. Siemeister, M. R. Schneider
Endocrine therapies available to block steroid hormone receptor-mediated tumor growth are based on two principles: ligand depletion and receptor blockade. Ligand depletion can be achieved either by removal of steroid-producing glands or by inhibition of steroid biosynthesis (inhibitors of aromatase, or gonadotropin-releasing hormone (GnRH) agonists). Estrogen receptors can be blocked either with selective estrogen receptor modulators (SERMs) or by a new class of compounds, the pure antiestrogens.
Radioautographic Localization of Estrogen Receptors in the Rat Uterus: A Tool for the Study of Classical and Nontraditional Mechanisms of Hormone Action
Published in Louis P. Pertschuk, Sin Hang Lee, Localization of Putative Steroid Receptors, 2019
Andrei N. Tchernitchin, Miguel A. Mena, Angel Rodriguez, Mauricio Maturana
Steroid hormone specificity — Each steroid hormone receptor is specific for its high-affinity binding to its own class of hormones. The concept of specificity implies high-affinity binding, since a steroid, when at very high concentrations, may also bind to receptors of different classes of hormones. At lower but still nonphysiologic concentrations, steroid receptors from some target organs may not be absolutely specific for their own class of hormones;128 this phenomenon may also occur at physiologic hormone concentrations,129 suggesting differences among the receptors from the different cell types. Accordingly, for an accurate characterization of any receptor, its spectrum of affinity should be described for the different compounds of its own class of hormones and also for compounds that do not belong to it. For glucocorticoids, a number of different receptors were reported differing in their spectra of affinity for different steroids;99”102 the possibility of heterogeneity may also exist for estrogen receptors in the different target cell types. Therefore, the spectra of affinity of estrogen receptors need to be investigated for each individual cell type. In radioautographic studies, steroid receptor specificity may be demonstrated in competition experiments as a decrease in hormone binding under the effect of different concentrations (or doses) of the competitor(s).
The Treatment of Early and Advanced Endometrial Carcinoma with Drugs and Hormones
Published in Nicholas Bruchovsky, James H. Goldie, Drug and Hormone Resistance in Neoplasia, 2019
No model has yet been developed that simply and adequately explains the ultimate mechanism of the antineoplastic effect of hormone therapy. The increased knowledge of steroid hormone receptor physiology gained in recent years allows some understanding of clinical observations of hormone effects. Nonetheless, the hormonal regulation of cell growth and death involve a highly complex mechanism which remains inadequately understood.66
Detection of endocrine and metabolism disrupting xenobiotics in milk-derived fat samples by fluorescent protein-tagged nuclear receptors and live cell imaging
Published in Toxicology Mechanisms and Methods, 2023
Keshav Thakur, Emmagouni Sharath Kumar Goud, Yashika Jawa, Chetan Keswani, Suneel Onteru, Dheer Singh, Surya P. Singh, Partha Roy, Rakesh K. Tyagi
Estrogen receptor α (ERα) also belongs to the steroid hormone receptor family. However, unlike AR, ligand-free ERα is predominantly localized in the nuclear compartment. This nuclear localized ERα cannot be used for studying ligand response via nuclear translocation assays as was possible with AR. However, specific mutations in the nuclear localization signal (NLS), region of NRs are reported to shift the localization of some ligand-free receptors (Guiochon-Mantel et al. 1989; Burns et al. 2011; Mavinakere et al. 2012; Rana et al. 2018; Lu et al. 2021). To obtain a cytoplasmic-shifted ERα chimera capable of responding to hormones and xenobiotics, we replaced selected residues (R263A, K266A, K268A, R269A, R271A) in the DNA binding domain-hinge region (DBD-Hinge) of GFP-ERα. This GFP-ERαcy was characterized by immunoblotting, immunocytochemistry, and transcription assays (data not shown). The cytoplasmic-shifted ERα mutant was found to be suitable for assessing the presence of (anti-)estrogenic xenobiotics by observing its nuclear translocation.
Factors influencing the anticancer effects of metformin on breast cancer outcomes: a systematic review and meta-analysis
Published in Expert Review of Anticancer Therapy, 2022
Hadeer Ehab Barakat, Raghda R. S. Hussein, Ahmed Abdullah Elberry, Mamdouh Ahmed Zaki, Mamdouh Elsherbiny Ramadan
Furthermore, the Patterson trial augmented the evidence of additive anticancer effect of metformin on weight loss, which was explained by four points. First, insulin receptor activation can accelerate BC cell growth and division, therefore high concentrations of circulating insulin can decrease survival time among patients with BC [84]. Second, high levels of estrogen lead to poor BC survival outcomes. Third, insulin and estrogens interact via inducing the expression of adipose stromal cell aromatase and tumor cell sex steroid hormone receptor, and by suppressing the expression of SHBG, which can increase estrogen synthesis and bioactivity and promote estrogen-dependent breast cancer [85]. Fourth, testosterone can increase the risk of BC directly or via aromatization to estradiol, which also increases the risk of BC cell proliferation [86]. Metformin and weight loss have favorable effects on insulin and sex hormone-binding globulin (SHBG) concentrations, and metformin also has favorable effects on estradiol and testosterone. Therefore patients with high BMI may experience improved survival outcome with metformin use [18,27,53]. This result is in agreement with the findings of the Ko trial, which concluded a beneficial effect of metformin on overweight/obese patients and on biomarkers linked to cancer risk [53].
Involvement of β-catenin in Androgen-induced Mesenchymal Transition of Breast MDA-MB-453 Cancer Cells
Published in Endocrine Research, 2021
Mamoun Ahram, Randa Bawadi, Mohammad S. Abdullah, Dana B. Alsafadi, Haneen Abaza, Sallam Abdallah, Ebtihal Mustafa
AR is a ligand-activated transcription factor that regulates the expression of numerous genes responsible for controlling cell proliferation and maturation.8 It is expressed in mammary tissue and plays important roles in the development of normal mammary glands.9–12 AR is the most widely expressed steroid hormone receptor in breast cancer with a higher prevalence among ER-positive tumors.13 In the context of ER-negative disease, the AR is expressed in 20–50% of the cases depending on the technique used (specifically, immunohistochemistry versus gene expression) and the studied population. In contrast to prostate cancer, the biological role of AR in breast cancer in general and in ER-negative/AR-positive subtype, in particular, has yet to be elucidated with preclinical studies reporting that AR has both proliferative and anti-proliferative effects.14–17