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Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer.

ABSTRACT: Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients.

SUBMITTER: Gallez A

PROVIDER: S-EPMC8160902 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundUnless women start effective contraception after oral emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies. We hypothesised that pharmacist provision of the progestogen-only pill as a bridging interim method of contraception with emergency contraception plus an invitation to a sexual and reproductive health clinic, in which all methods of contraception are available, would result in increased subsequent use of effective contraception.MethodsWe did a pragmatic cluster-randomised crossover trial in 29 UK pharmacies among women receiving levonorgestrel emergency contraception. Women aged 16 years or older, not already using hormonal contraception, not on medication that could interfere with the progestogen-only pill, and willing to give contact details for follow-up were invited to participate. In the intervention group, women received a 3-month supply of the progestogen-only pill (75 μg desogestrel) plus a rapid access card to a participating sexual and reproductive health clinic. In the control group, pharmacists advised women to attend their usual contraceptive provider. The order in which each pharmacy provided the intervention or control was randomly assigned using a computer software algorithm. The primary outcome was the use of effective contraception (hormonal or intrauterine) at 4 months. This study is registered, ISRCTN70616901 (complete).FindingsBetween Dec 19, 2017, and June 26, 2019, 636 women were recruited to the intervention group (316 [49·6%], mean age 22·7 years [SD 5·7]) or the control group (320 [50·3%], 22·6 years [5·1]). Three women (one in the intervention group and two in the control group) were excluded after randomisation. 4-month follow-up data were available for 406 (64%) participants, 25 were lost to follow-up, and two participants no longer wanted to participate in the study. The proportion of women using effective contraception was 20·1% greater (95% CI 5·2-35·0) in the intervention group (mean 58·4%, 48·6-68·2), than in the control group (mean 40·5%, 29·7-51·3 [adjusted for recruitment period, treatment group, and centre]; p=0·011).The difference remained significant after adjusting for age, current sexual relationship, and history of effective contraception use, and was robust to the effect of missing data (assuming missingness at random). No serious adverse events occurred.InterpretationProvision of a supply of the progestogen-only pill with emergency contraception from a community pharmacist, along with an invitation to a sexual and reproductive health clinic, results in a clinically meaningful increase in subsequent use of effective contraception. Widely implemented, this practice could prevent unintended pregnancies after use of emergency contraception.FundingNational Institute for Health Research (Health Technology Assessment Programme project 15/113/01).

Project description:BackgroundAltered lipid metabolism is an emerging hallmark of aggressive breast cancers. The N-myc downstream regulated gene (NDRG1) gene plays a critical role in peripheral nervous system myelination, as inactivating mutations cause severe demyelinating neuropathy. In breast cancer, elevated NDRG1 expression has been linked to clinical outcomes, but its functional role in breast cancer physiology has remained unclear.MethodsA meta-analysis of NDRG1 expression in multiple large publicly available genomic databases was conducted. Genome-wide expression correlation and Cox proportional hazards and Kaplan-Meier modeling of clinical outcomes associated with elevated expression were assessed. To study NDRG1 function, gene silencing and overexpression phenotypic studies were carried out in a panel of cell lines representing all major breast cancer molecular subtypes. Changes in cell proliferation, morphology, and neutral lipid accumulation due to altered NDRG1 expression were assessed by high throughput, quantitative microscopy. Comprehensive lipidomics mass spectrometry was applied to characterize global changes in lipid species due to NDRG1 silencing. Labeled fatty acids were used to monitor cellular fatty acid uptake and subcellular distribution under nutrient replete and starvation culture conditions.ResultsNDRG1 overexpression correlated with glycolytic and hypoxia-associated gene expression, and was associated with elevated rates of metastasis and patient mortality. Silencing NDRG1 reduced cell proliferation rates, causing lipid metabolism dysfunction including increased fatty acid incorporation into neutral lipids and lipid droplets. Conversely, NDRG1 expression minimized lipid droplet formation under nutrient replete and starvation conditions.ConclusionsHere we report that NDRG1 contributes to breast cancer aggressiveness by regulating the fate of lipids in cells that exhibit an altered lipid metabolic phenotype. In line with its role in promoting myelination and its association with altered metabolism in cancer, our findings show that NDRG1 is a critical regulator of lipid fate in breast cancer cells. The association between NDRG1 and poor prognosis in breast cancer suggests it should play a more prominent role in patient risk assessment. The function of NDRG1 in breast cancer lipid metabolism may represent a promising therapeutic approach in the future.

Project description:BackgroundMenarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.MethodsIndividual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.FindingsBreast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).InterpretationThe effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.FundingCancer Research UK.

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Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer.

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