Implication du récepteur aux oestrogènes ERalpha dans les maladies reproductives chez la femme : le cancer du sein et l'endométriose

L'expression des récepteurs aux oestrogènes (ER) et en particulier de ERa semble être un facteur clés dans la prise en charge de l'endométriose et du cancer du sein. Le cancer du sein est sous l'influence du 17ß-œstradiol (E2) par le biais des ER, en particulier ERa. Outre la forme de pleine taille (66kDa), il existe une forme de 46kDa dépourvue de la fonction de transactivation AF1. Le niveau d'expression et le rôle de cette isoforme restent jusqu'ici inexplorés. 1) Par une étude en immunohistochimie (IH) et en western blot (WB) nous avons montré que les anticorps utilisés dans le diagnostic du cancer du sein ne permettent pas de détecter ERa46 ; 2) Dans une cohorte de 116 patientes, nous avons étudié l'expression d'ERa46 dans les tumeurs mammaires humaines en WB et mis en évidence une expression présente dans plus de 70% des cas, avec une surexpression dans les tumeurs de meilleur pronostic ; 3) Nous avons étudié le rôle d'AF1 dans la carcinogenèse mammaire dans des modèles murins PyMT, surexprimant ou non l'isoforme ERa46 et mis en évidence un probable rôle protecteur de la délétion d'AF1 lors de la carcinogénèse débutante, puis une inversion à un stade plus tardif, avec un effet péjoratif de l'expression d'ERa46, sur le volume tumoral, la croissance tumorale et le stade histologique ; 4) Enfin, une étude du rôle d'ERa46 dans le processus métastatique chez la femme a été réalisé par une analyse comparative en Western wes, de son expression dans les tumeurs primitives, les récidives locorégionales et à distance. Les résultats montrent une diminution de l'expression d'ERa46 entre la tumeur initiale et la récidive dans les récidives précoces. Une étude rétrospective sur la cohorte de 116 patientes rejoint l'hypothèse des résultats de l'étude murine, avec des récidives plus fréquentes chez les patientes ayant eu une surexpression de ERa46 au diagnostic. Il est donc licite de se poser la question d'une éventuelle instabilité de l'expression des 2 isoformes lors du processus de carcinogénèse. En effet, l'expression de l'isoforme courte semble avoir un effet protecteur dans la phase initiale de la maladie, puis, un effet péjoratif dans l'évolution du processus tumoral, qui pourrait être la conséquence d'une instabilité plus importante de ERa46 que de celle de ERa66. L'endométriose est une maladie inflammatoire œstrogéno-dépendante, bénigne grave, touchant 6 à 10% des femmes en âge de procréer et définie par la présence de tissu endométrial ectopique. La production élevée d'œstrogènes est une des caractéristiques de cette pathologie. Bien qu'il existe un grand nombre de données concernant les ER, notre compréhension des rôles de ERa et ERß dans cette pathologie reste incomplète avec des données de la littérature peu comparables basées sur des modèles endométriosiques différents, des lésions d'endométriosiques d'origine anatomiques variables et la validation d'anticorps remise en question. La phase d'initiation avec la survie et l'invasion du tissu endométrial ectopique est incomprise. Le système immunitaire pourrait être le chaînon manquant dans l'initiation de la maladie de façon couplée à l'oestrogéno-dépendance. 1) Nous avons ainsi réalisé une revue de la littérature, rapportant que ERß et ERa semblent agir de manières différentes pour favoriser la prolifération et l'invasion. 2) Les résultats préliminaires d'une étude en IH et en WB sur des lésions endométriosiques, avec des anticorps validés, de l'expression d'ERß et ERa, montrent une expression significative d'Era. 3) Enfin, une étude de la population immunitaire dans le liquide péritonéal a été réalisée sur une cohorte de patientes (n=16) opérées pour des lésions d'endométriose en comparaison à une cohorte de patientes saines (n=15). Une dérégulation de l'immunité des patientes atteintes d'endométriose a été mise en évidence avec une augmentation de certaines populations lymphocytaires qu'il reste à caractériser pour mieux les cibler d'un point de vue thérapeutique.Estrogen receptors (ER) expression and in particular ERa appears to be a key factor in the management of endometriosis and breast cancer. Breast cancer is influenced by 17ß-estradiol (E2) through ERs, in particular ERa. In addition to the full-length form (66kDa), there is a 46kDa form that lacks the AF1 transactivating function. The level of expression and the role of this isoform remain unexplored so far. 1) By a study in immunohistochemistry (IH) and western blot (WB), we showed that the antibodies used in the diagnosis of breast cancer do not allow the detection of ERa46; 2) In a cohort of 116 patients, we studied the expression of ERa46 in human breast tumors in WB and demonstrated an expression in more than 70% of cases, with overexpression in tumors with better prognosis; 3) We studied the role of AF1 in breast carcinogenesis in PyMT mouse models, overexpressing or not the isoform ERa46 and demonstrated a likely protective role of AF1 deletion in early carcinogenesis, then an inversion at a later stage, with a pejorative effect of the ERa46 expression on tumor volume, tumor growth and histological stage; 4) Finally, a study of the role of ERa46 in the metastatic process in women was carried out by a comparative analysis in Western wes, of its expression in primary tumors, local recurrence and distant metastases. The results show a decrease in the expression of ERa46 between the initial tumor and recurrence when they are early. A retrospective study of the cohort of 116 patients joins the hypothesis of the results of the murine study, with more frequent recurrences in patients who had an overexpression of ERa46 at diagnosis. It is therefore legitimate to ask the question of a possible instability of the expression of the 2 isoforms during the process of carcinogenesis. Indeed, the expression of the short isoform seems to have a protective effect in the initial phase of the disease, then a pejorative effect in the evolution of the tumor process, which could be the consequence of a greater instability of ERa46 than of ERa66. Endometriosis is a severe, benign, estrogen-dependent inflammatory disease affecting 6-10% of women of childbearing age and defined by the presence of ectopic endometrial tissue. High estrogen production is the characteristics feature of this disease. Although there is a large amount of data concerning ERs, our understanding of the roles of ERa and ERß in this pathology remains incomplete with poorly comparable in the literature based on different endometriotic models, endometriotic lesions of variable anatomical origin and questioned antibodies validation. The initiation phase with survival and invasion of the ectopic endometrial tissue is not understood. The immune system may be the missing link in the initiation of the disease coupled with estrogen dependence. 1) We thus conducted a review of the literature, reporting that ERß and ERa seem to act in different ways to promote proliferation and invasion. 2) Preliminary results of an IH and WB study on endometriotic lesions, with validated antibodies, of the expression of ERß and ERa, show a significant expression of ERa. 3) Finally, a study of the immune population in the peritoneal fluid was carried out on a cohort of patients (n = 16) operated for endometriosis lesions compared to a cohort of healthy patients (n = 15). A deregulation of the immunity of patients with endometriosis has been demonstrated with an increase in certain lymphocyte populations which remain to be characterized in order to better target them from a therapeutic point of view

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

International audience17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice

Metabolic activity determines survival depending on the level of lymph node involvement in cervical cancer

Abstract Background To assess the impact of PET/CT functional parameters on survival, locoregional, and distant failure according to the most distant level of lymph node [18F]FDG uptake in patients with locally advanced cervical cancer (LACC). Methods Retrospective study including 148 patients with LACC treated with concurrent chemoradiotherapy after PET/CT and para-aortic lymph node (PALN) surgical staging. Two senior nuclear medicine physicians reviewed all PET/CT exams and retrieved tumor and lymph node metabolic parameters: SUVmax, MTV, TLG. Oncological outcomes according to metabolic parameters and level of lymph node spread on PET/CT were assessed. Results In patients without lymph node uptake on PET/CT, high MTV values of the cervical tumor were associated with DFS (HR = 5.14 95%CI = [2.15–12.31]), OS (HR = 6.10 95%CI = [1.89–19.70]), and time to distant (HR = 4.73 95%CI = [1.55–14.44]) and locoregional recurrence (HR = 5.18 95%CI = [1.72–15.60]). In patients with pelvic lymph node (PLN) uptake but without PALN uptake on [18F]FDG-PET/CT, high MTV values of the cervical tumor were associated with DFS (HR = 3.17 95%CI = [1.02–9.83]) and OS (HR = 3.46 95%CI = [0.96–12.50]), and the number of PLN fixations was associated with DFS (HR = 1.30 95%CI = [1.10–1.53]), OS (HR = 1.35 95%CI = [1.11–1.64]), and time to distant (HR = 1.35 95%CI = [1.08–1.67]) and locoregional recurrence (HR = 1.31 95%CI = [1.08–1.59]). There was no significant association between cervical tumor metabolic or lymph node metrics and survival outcome in patients with PALN uptake. Conclusions Cervical MTV is more accurate than SUVmax to predict survival outcome in patients with locoregional disease confined to the pelvis and should be implemented in routine clinical practice. Prognostic value of metabolic metrics disappears with PALN uptake, which is associated with distant failure in nearly half of patients. Graphical Abstrac

Perineal Wound Closure Following Abdominoperineal Resection and Pelvic Exenteration for Cancer: A Systematic Review and Meta-Analysis

International audienceBackground. Abdominoperineal resection (APR) and pelvic exenteration (PE) for thetreatment of cancer require extensive pelvic resection with a high rate of postoperative complications.The objective of this work was to systematically review and meta-analyze the effects of vertical rectusabdominis myocutaneous flap (VRAMf) and mesh closure on perineal morbidity following APR andPE (mainly for anal and rectal cancers). Methods. We searched PubMed, Cochrane, and EMBASE foreligible studies as of the year 2000. After data extraction, a meta-analysis was performed to compareperineal wound morbidity. The studies were distributed as follows: Group A comparing primaryclosure (PC) and VRAMf, Group B comparing PC and mesh closure, and Group C comparing PCand VRAMf in PE. Results. Our systematic review yielded 18 eligible studies involving 2180 patients(1206 primary closures, 647 flap closures, 327 mesh closures). The meta-analysis of Groups A and Bshowed PC to be associated with an increase in the rate of total (Group A: OR 0.55, 95% CI 0.43–0.71;p < 0.01/Group B: OR 0.54, CI 0.17–1.68; p = 0.18) and major perineal wound complications (Group A:OR 0.49, 95% CI 0.35–0.68; p < 0.001/Group B: OR 0.38, 95% CI 0.12–1.17; p < 0.01). PC was associatedwith a decrease in total (OR 2.46, 95% CI 1.39–4.35; p < 0.01) and major (OR 1.67, 95% CI 0.90–3.08;p = 0.1) perineal complications in Group C. Conclusions. Our results confirm the contribution of theVRAMf in reducing major complications in APR. Similarly, biological prostheses offer an interestingalternative in pelvic reconstruction. For PE, an adapted reconstruction must be proposed withspecialized expertise

Estrogen Receptors and Endometriosis

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ER&beta; and significantly lower ER&alpha; levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ER&alpha; and ER&beta; in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies

The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors

International audienceBackground - To date, all studies conducted on breast cancer diagnosis have focused on the expression of the full-length 66-kDa estrogen receptor alpha (ERα66). However, much less attention has been paid to a shorter 46-kDa isoform (ERα46), devoid of the N-terminal region containing the transactivation function AF-1. Here, we investigated the expression levels of ERα46 in breast tumors in relation to tumor grade and size, and examined the mechanism of its generation and its specificities of coregulatory binding and its functional activities.Methods - Using approaches combining immunohistochemistry, Western blotting, and proteomics, antibodies allowing ERα46 detection were identified and the expression levels of ERα46 were quantified in 116 ERα-positive human breast tumors. ERα46 expression upon cellular stress was studied, and coregulator bindings, transcriptional, and proliferative response were determined to both ERα isoforms.Results - ERα46 was expressed in over 70% of breast tumors at variable levels which sometimes were more abundant than ERα66, especially in differentiated, lower-grade, and smaller-sized tumors. We also found that ERα46 can be generated via internal ribosome entry site-mediated translation in the context of endoplasmic reticulum stress. The binding affinities of both unliganded and fully-activated receptors towards co-regulator peptides revealed that the respective potencies of ERα46 and ERα66 differ significantly, contributing to the differential transcriptional activity of target genes to 17β estradiol (E2). Finally, increasing amounts of ERα46 decrease the proliferation rate of MCF7 tumor cells in response to E2.Conclusions - We found that, besides the full-length ERα66, the overlooked ERα46 isoform is also expressed in a majority of breast tumors. This finding highlights the importance of the choice of antibodies used for the diagnosis of breast cancer, which are able or not to detect the ERα46 isoform. In addition, since the function of both ERα isoforms differs, this work underlines the need to develop new technologies in order to discriminate ERα66 and ERα46 expression in breast cancer diagnosis which could have potential clinical relevance.<br