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Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. β-adrenergic receptors (β-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in β-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of β-AR. To study regulation of the breast cell phenotype by β-AR, we over-expressed β-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down β-AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the β-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that β-AR expression level is a key player in cell behavior. β-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of β-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER-independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERα, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through β-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally, this differentiating effect could be resourceful in a breast tumor context. [ABSTRACT FROM AUTHOR]

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters. [ABSTRACT FROM AUTHOR]

Background: In 30 years of experience in responding to the HIV epidemic, critical decisions and program characteristics for successful scale-up have been studied. Now leaders face a new challenge: sustaining large-scale HIV prevention programs. Implementers, funders, and the communities served need to assess what strategies and practices of scaling up are also relevant for sustaining delivery at scale. Methods: We reviewed white and gray literature to identify domains central to scaling-up programs and reviewed HIV case studies to identify how these domains might relate to sustaining delivery at scale. Results: We found 10 domains identified as important for successfully scaling up programs that have potential relevance for sustaining delivery at scale: fiscal support; political support; community involvement, integration, buy-in, and depth; partnerships; balancing flexibility/adaptability and standardization; supportive policy, regulatory, and legal environment; building and sustaining strong organizational capacity; transferring ownership; decentralization; and ongoing focus on sustainability. We identified one additional potential domain important for programs sustaining delivery at scale: emphasizing equity. Conclusions: Today, the public and private sector are examining their ability to generate value for populations. All stakeholders are aiming to stem the tide of the HIV epidemic. Implementers need a framework to guide the evolution of their strategies and management practices. Greater research is needed to refine the domains for policy and program implementers working to sustain HIV program delivery at scale.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator used for emergency contraception that has proven to be highly effective in preventing pregnancy when taken up to 120 h after unprotected sexual intercourse. Even though it may act mainly by delaying or inhibiting ovulation, additional effects of UPA on post-fertilization events cannot be excluded. Therefore, the aim of this study was to determine whether a single post-ovulatory dose of UPA could prevent pregnancy using the mouse as a pre-clinical model. Mated females received a single dose of UPA (40 mg/kg) on Day E1.5 or E2.5 (E0.5: copulatory plug detection) and post-fertilization events were evaluated. Our studies revealed that UPA administration produced a significant decrease in the number of conceptuses compared to control. Moreover, UPA-treated females exhibited a lower number of early implantation sites on Day E5.5, despite normal in vivo embryo development and transport to the uterus at E3.5. Administration of UPA produced histological and functional alterations in the uterine horns, i.e., a dyssynchronous growth between endometrial glands and stroma, with non-physiological combination of both fractions compared to controls, and a completely impaired ability to respond to an artificial decidualization stimulus. Altogether, our results show that the administration of a single post-ovulatory dose of UPA impairs mouse pregnancy probably due to an effect on embryo-uterine interaction, supporting additional effects of the drug on post-fertilization events. Although these studies cannot be performed with human samples, our results with the mouse model provide new insights into the mechanism of action of UPA as an emergency contraception method., (© The Author 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics., Methods: We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided., Results: One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P <  .001). PRB-H tumors showed increased tumor size ( P <  .001), Ki-67 levels ( P <  .001), human epidermal growth factor receptor 2 expression ( P =  .04), high grades ( P =  .03), and decreased total PR ( P =  .004) compared with PRA-H tumors. MUC-2 ( P <  .001) and KRT6A ( P =  .02) were also overexpressed in PRB-H tumors., Conclusion: The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Can the bioactive lipid sphingosine-1 phosphate (S1P) act as an endothelial barrier-enhancing molecule and, in turn, restore the vascular integrity and homoeostasis in a rat model of ovarian hyperstimulation syndrome (OHSS)., Study Answer: In vivo administration of S1P may prevent the early onset of OHSS and decrease its severity., What Is Known Already: Although advances in the prediction and treatment of OHSS have been made, complete prevention has not been possible yet. S1P in follicular fluid from women at risk of developing OHSS are lower in comparison from women who are not at such risk and administration of S1P in an OHSS rat model decreases ovarian capillary permeability., Study Design, Size, Duration: We used an animal model that develops OHSS in immature Sprague-Dawley rats. The rats were randomly divided into three groups: the control group, which was injected with 10 IU of pregnant mare's serum gonadotropin (PMSG), and 10 IU of hCG 48 h later; the OHSS group, which was injected with excessive doses of PMSG (50 IU/day) for four consecutive days, followed by hCG; and the OHSS + S1P group, which was injected with the same doses of PMSG and hCG as the OHSS group and then treated with 5 μl S1P (1 mM) under the bursa of both ovaries, whereas the other groups of animals received the S1P vehicle., Participants /materials, Setting, Methods: Rats were killed by decapitation 48 h after the hCG injection for ovary, endometrium and blood collection. The ovaries were weighed and then used for subsequent assays, while the serum was used for hormone assays. One of the ovaries from each rat (n = 6) was used for Western immunoblot and the other for immunohistochemical analysis. Statistical comparisons between groups were carried out., Main Results and the Role of Chance: S1P administration reduced the ovarian weight (P < 0.05), and decreased the concentration of serum progesterone in the OHSS group compared to the OHSS group without treatment (P < 0.001). The percentage of antral follicles in the OHSS group was lower than that in the control group. S1P increased the percentage of antral follicles (P < 0.05) and decreased the percentage of corpora lutea (P < 0.01) and cystic structures in the OHSS group (P < 0.05). S1P had no effect on the expression levels of the enzymes 3β-hydroxysteroid dehydrogenase (3βHSD) or cholesterol side-chain cleavage enzyme (P450scc), but reduced the levels of steroidogenic acute regulatory protein (StAR) in OHSS rat ovaries (P < 0.05). S1P decreased the endothelial (P < 0.05) and periendothelial (P < 0.01) cell area in OHSS rat ovaries. S1P restored the levels of N-cadherin and VE-cadherin proteins to control values. Furthermore, S1P enhanced the levels of claudin-5, occludin (P < 0.05) and sphingosine-1-phosphate receptor 1 (S1PR1) in OHSS (P < 0.01). In addition, no histological differences were found in endometrium between OHSS and S1P-treated OHSS animals., Limitations Reasons for Caution: The results of this study were generated from an in vivo OHSS experimental model, which has been used by several authors and our group due to the similarity between the rat and human angiogenic systems. Further studies in patients will be needed to evaluate the effects of S1P in the pathogenesis of OHSS., Wider Implications of the Findings: These findings concern the pathophysiological importance of S1P in OHSS. More studies on the regulation of endothelial cell barrier function by S1P in reproductive pathological processes and its therapeutic application are required., Large Scale Data: N/A., Study Funding and Competing Interest(s): This work was supported by grants from ANPCyT (PICT 2012-897), CONICET (PIP 5471), Roemmers and Baron Foundations, Argentina. The authors declare no conflicts of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The federal government has implemented several strategies to reduce mortality caused by chronic non-communicable diseases (CNTD). One example is the development of medical units specialized in the care of CNTD (i.e. overweight, obesity, cardiovascular risk and diabetes), named UNEMES (from its Spanish initials). These units--consisting of an ad-hoc, trained, multi-disciplinary team--will provide patient education, help in the resolution of obstacles limiting treatment adherence, and involve the family in patient care. Treatment will be provided using standardized protocols. The efficacy of the intervention will be regularly measured using pre-specified outcomes. We expect that these UNEMES will result in significant savings. In summary, our health care system is developing better treatment strategies for CNTD. Evaluating the performance of the UNEMES will generate valuable information for the design of future preventive actions.