Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE155274 | GEO | 2021/05/12
REPOSITORIES: GEO
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Project description:Hormonal contraception exposes women to different synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect cell proliferation in the normal breast epithelium and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins strongly induce the PR target and mediator of PR signaling induced cell proliferation Receptor Activator of NF-κB Ligand (Rankl), previously implicated in breast carcinogenesis, whereas other progestins fail to do so. We developed xenografts of normal human breast epithelial cells (HBECSs) to the milk ducts of immunocompromised female mice and show that they remain hormone-responsive. Using HBECSs from 36 women, we show that testosterone-related progestins, desogestrel, gestodene, and levonorgestrel, induce PSA (KLK3) and promote their proliferation, whereas the anti-androgenic progestins, which have shown anti-androgenic properties in reporter assays, chlormadinone acetate and cyproterone acetate, do not. Pharmacological inhibition of the androgen receptor (AR) inhibits PR agonist and levonorgestrel-induced RANKL expression and both pharmacological and genetic AR inhibition reduce levonorgestrel-driven breast epithelial cell proliferation in vivo. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Thus, different progestins have distinct biological activities in the breast epithelium that should be taken into account for more informed choices in hormonal contraception.
2021-05-12 | GSE155273 | GEO
Project description:Hormonal contraception exposes women to different synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect cell proliferation in the normal breast epithelium and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins strongly induce the PR target and mediator of PR signaling induced cell proliferation Receptor Activator of NF-κB Ligand (Rankl), previously implicated in breast carcinogenesis, whereas other progestins fail to do so. We developed xenografts of normal human breast epithelial cells (HBECSs) to the milk ducts of immunocompromised female mice and show that they remain hormone-responsive. Using HBECSs from 36 women, we show that testosterone-related progestins, desogestrel, gestodene, and levonorgestrel, induce PSA (KLK3) and promote their proliferation, whereas the anti-androgenic progestins, which have shown anti-androgenic properties in reporter assays, chlormadinone acetate and cyproterone acetate, do not. Pharmacological inhibition of the androgen receptor (AR) inhibits PR agonist and levonorgestrel-induced RANKL expression and both pharmacological and genetic AR inhibition reduce levonorgestrel-driven breast epithelial cell proliferation in vivo. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Thus, different progestins have distinct biological activities in the breast epithelium that should be taken into account for more informed choices in hormonal contraception.
2021-05-12 | GSE155272 | GEO
Project description:Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties.
| PRJNA649228 | ENA
Project description:Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [human]
| PRJNA649233 | ENA
Project description:Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [mouse]
| PRJNA649234 | ENA
Project description:Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins induce the PR target and mediator of PR signaling-induced cell proliferation receptor activator of NF-κB ligand (Rankl), whereas progestins with anti-androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone-responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti-androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist- and levonorgestrel-induced RANKL expression and reduces levonorgestrel-driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception.
| S-EPMC8261488 | biostudies-literature
Project description:Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins induce the PR target and mediator of PR signaling-induced cell proliferation Receptor Activator of NF-?B Ligand (Rankl) whereas progestins with anti-androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone-responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti-androgenic, chlormadinone and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist- and levonorgestrel-induced RANKL expression and reduces levonorgestrel-driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception.
| S-SCDT-EMM-2021-14314P | biostudies-other
Project description:Progestins used in endocrine therapies bind to multiple steroid receptors and are associated with several side-effects. It is thus important to understand the relationship between steroid receptor cross-reactivity and the side-effect profile of progestins. In cell lines that express negligible levels of steroid receptors, we report for the first time the binding affinities, potencies and efficacies of selected progestins from different generations determined in parallel. We show that the progestins bind to the androgen receptor (AR) with similar affinities to each other and progesterone, while none bind estrogen receptor (ER)-?, and only norethisterone acetate, levonorgestrel and gestodene bind ER?. Comparative dose-response analysis revealed that progestins from the first three generations display similar androgenic activity to the natural androgen dihydrotestosterone for transactivation, while norethisterone acetate, levonorgestrel and gestodene are ER? agonists. We show for the first time that the anti-androgenic properties of progesterone and drospirenone are similar to the well-known AR antagonist hydroxyflutamide, while nomegestrol acetate is more potent and nestorone less potent than both hydroxyflutamide and progesterone. Moreover, we are the first to report that the older progestins, unlike progesterone and the fourth generation progestins, are efficacious ER? agonists for transrepression, while the selected progestins from the second and third generation are efficacious AR agonists for transrepression. Considering the progestin potencies and their reported free serum concentrations relative to dihydrotestosterone and estradiol, our results suggest that the progestins are likely to exert AR-, but not ER?- or ER?-mediated effects in vivo.
| S-EPMC5740213 | biostudies-literature
Project description:Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.
| S-EPMC5916247 | biostudies-literature
Project description:BACKGROUND: Cell migration plays an essential role in many biological processes, such as cancer metastasis, wound healing and immune response. Cell migration is mediated through protrusion and focal adhesion (FA) assembly, maturation and disassembly. Epidermal growth factor (EGF) is known to enhance migration rate in many cell types; however it is not known how FA maturation, FA dynamics and protrusion dynamics are regulated during EGF-induced migration. Here we use total internal reflection fluorescence (TIRF) microscopy and image analysis to quantify FA properties and protrusion dynamics under different doses of EGF stimulation. RESULTS: EGF was found to broaden the distribution of cell migration rates, generating more fast and slow cells. Furthermore, groups based on EGF stimulation condition or cell migration speed were marked by characteristic signatures. When data was binned based on EGF stimulation conditions, FA intensity and FA number per cell showed the largest difference among stimulation groups. FA intensity decreased with increasing EGF concentration and FA number per cell was highest under intermediate stimulation conditions. No difference in protrusion behavior was observed. However, when data was binned based on cell migration speed, FA intensity and not FA number per cell showed the largest difference among groups. FA intensity was lower for fast migrating cells. Additionally, waves of protrusion tended to correlate with fast migrating cells. CONCLUSIONS: Only a portion of the FA properties and protrusion dynamics that correlate with migration speed, correlate with EGF stimulation condition. Those that do not correlate with EGF stimulation condition constitute the most sensitive output for identifying why cells respond differently to EGF. The idea that EGF can both increase and decrease the migration speed of individual cells in a population has particular relevance to cancer metastasis where the microenvironment can select subpopulations based on some adhesion and protrusion characteristics, leading to a more invasive phenotype as would be seen if all cells responded like an "average" cell.
| S-EPMC3414788 | biostudies-other