INTRODUCTION Estrogen is implicated as an important factor in stimulating breast cancer cell proliferation, and presence of estrogen receptor (ER) is an indication of a good prognosis in breast cancer patients. Mcl-1 is an anti-apoptotic Bcl-2 family member that is often overexpressed in breast tumors, correlating with poor survival. Estrogen has been previously shown to regulate Bcl-2 family members, leading to an evasion of apoptosis, however the role of estrogen in regulating Mcl-1 expression is unclear. I hypothesize that estrogen increases the expression of anti-apoptotic gene Mcl-1 through binding of ERα to a half estrogen response element (ERE) site within the promoter of Mcl-1 gene. This leads to increased Mcl-1 expression in breast cancer cells, ultimately contributing to an evasion of apoptosis. METHODS Four distinct breast cancer cell lines: MCF-7 and ZR-75, which both express ERα, and SKB-BR-3 and MDA-MB-231, which do not express ERα, to investigate the role of estrogen plays in regulating Mcl-1 expression. Cells were grown in serum-starved white media with charcoal-stripped FBS for five days prior to treatment with estrogen. Cells were treated with ERα antagonists Tamoxifen and Fulvestrant in combination with estrogen. Also, siRNA knockdown of ERα was performed and mRNA expression was evaluated. Chromatin immunoprecipitation (ChIP) was used to investigate if ERα binds to a specific ERE halfsite within the Mcl-1 promoter. To further validate this data, a streptavidin pull-down assay was performed using a biotinlabeled probe specific to this region. RESULTS In ERα positive cell lines, estrogen treatment increased Mcl-1 expression at both the protein and mRNA level. In two ERα negative cell lines, SK-BR-3 and MDA-MB-231, estrogen failed to increase in Mcl-1 protein expression. ERα antagonists decreased estrogen mediated Mcl-1 expression at both the protein and message level. Upon knockdown of ERα, Mcl-1 mRNA expression after estrogen treatment was also decreased. ChIP showed an enrichment of ERα to the Mcl-1 promoter at a region 3683 bp upstream of the translation start site containing a half ERE site. Streptavidin-pull down assay showed both ERα and transcription factor Sp1 bind to this region and mutation of the half ERE site eliminated this binding. CONCLUSIONS These results suggest that estrogen is involved in regulating Mcl-1 expression specifically through a mechanism involving ERα. Ultimately, a better understanding of the role of estrogen in regulating Mcl-1 expression will determine whether Mcl-1 is a valid molecular target for breast cancer therapy.

Contexte : les hormones œstrogéniques ont de nombreux effets protecteurs au niveau cardiovasculaire et rénal mais leurs mécanismes sont très complexes. Le récepteur aux œstrogènes ERα est le principal effecteur des effets bénéfiques de ces hormones. Il possède deux voies d’action. Dans le noyau, il a des effets génomiques via ses fonctions d’activation AF. A la membrane, il a des effets non-génomiques via une signalisation membranaire MISS. Première étude : dans une première étude, nous avons exploré le mécanisme protecteur d’ERα dans l’hypertension artérielle, un facteur de risque majeur de maladies cardiovasculaires. Nous avons mis en évidence le rôle protecteur des effets génomiques d’ERα via sa fonction AF-2 contre l’hypertension. Nous avons également observé que la stimulation de cette fonction par l’Estétrol suffisait à reproduire les effets protecteurs des œstrogènes, ce qui ouvre une perspective thérapeutique potentielle. Deuxième étude : dans une deuxième partie, nous avons étudié l’effet protecteur d’ERα dans le vieillissement cardiovasculaire et rénal. Cette étude, toujours en cours, a pu mettre en évidence que la souris femelle ne présentait pas d’altération majeure de la fonction vasculaire et rénale . Toutefois, le récepteur ERα ne semble pas impliqué dans cette protection vis-à-vis du vieillissement. Cette étude a toutefois permis de mettre en évidence que les œstrogènes agissaient sur la biogénèse mitochondriale, d’une manière inattendue. Ces résultats seront approfondis dans de prochaines expériences.Conclusion En conclusion, ce travail de thèse a permis de mieux cerner l’implication des hormones œstrogéniques et de leur récepteur ERα dans le système cardiovasculaire. / Context : estrogenic hormones have numerous beneficial effects in the cardiovascular and renal systems but the underlying mechanisms are extensively complex. Estrogen receptor ERα is described as the main effector of the positive actions of estrogens. This receptor acts in the cell using two different pathways. In the nucleus, ERα acts as a transcription factor with genomic effects, through its activating functions AF. At the membrane, it exerts non-genomic effects, called MISS. First Study : in a first study, we have explored the protective mechanism of ERα in hypertension, a main risk factor in cardiovascular diseases. Using genetically modified mice, we have been able to highlight the involvement of AF-2 genomic actions against angiotensin II-induced hypertension. On the other hand, ERα-dependant MISS was not involved in ERα protection. Confirming our hypothesis, we found that AF-2 stimulation with estetrol was sufficient to completely prevent hypertension, thus providing a possible therapeutic perspective. Second Study : in a second project, we have investigated the protective actions of ERα against aging-related cardiovascular and renal alterations. This work is still ongoing but we found that 16 months-old female mice presented no obvious vascular or renal dysfunctions. Those results are surprising considering past published data on the subject. Aging mice lacking ERα-/-did not exhibit any particular alterations either. However, we were able to find that estrogens and ERs were involved in the mitochondria biogenesis in a surprising manner. These results will be further investigated in the future. Conclusion : to conclude, this work has allowed a better understanding of the estrogens receptors actions in the cardiovascular and renal systems

Alternative splicing is a process that partly rejects the common definition of a gene – that one gene codes for one specific protein. By variable combination of coding regions (exons) and exclusion of non-coding regions (introns), formation of several different mRNA-transcripts, and consequently several different proteins, can derive from the same gene. Alternative splicing is an important condition for the development of complex life forms, but it is also a highly sensitive process and inaccurate splicing is the cause of approximately 15 % of mutations that cause genetic diseases. This article presents four genes, BRCA1, BRCA2, ERα and ERβ, and inaccurate splicing of these genes increases the risk of developing cancer, particularly breast cancer and ovarian cancer. Breast cancer is the second most common form of lethal cancer among women. After identifying the cancerogenic mutations, women of high-risk families can undergo genetic testing and preventive therapy can reduce the morbidity and mortality. The article also presents a short discussion around the ethical problems of genetic testing, and the social and psychological dilemmas women of high-risk families are facing when they are given the option to undergo genetic testing.

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Hintergrund: Die Gustafsson sche Yin-Yang-Theorie sagt dem stimulierten Östrogenrezeptors β hemmende oder modulierende Funktionen nach. Diese Studie untersuchte die Wirkungen der Kombination aus dem selektiven Östrogenrezeptoragonisten α (16α-LE2) und β (8β-VE2) sowie der Kombination aus Östradiol und dem ERβ-Agonist an 3 Monate alten ovarektomierten Sprague-Dawley-Ratten. Die subkutane Verabreichung erfolgte für insgesamt vier Wochen in kontinuierlich simultaner und zeitversetzt zweiwöchiger, simultaner Kombination. Eine Östradiolgruppe diente als Positivkontrolle. Als physiologischer Vergleichsparameter galt eine intakte sham-ovx Gruppe. Anhand von histologischen Schnitten und Hämatoxylin-Eosin-Färbung wurden der Uterus und die Vagina auf proliferative Effekte und histomorphologisch untersucht. Zusätzlich wurden das Uterusgewicht, die Futteraufnahme, das Körpergewicht und mittels RIA der Hormonhaushalt (Östradiol, LH, TSH, fT3 und fT4) beurteilt. Die kontinuierlich verabreichten Kombinationen aus E2 bzw. dem ERα-Agonisten und dem ERβ-Agonisten präsentierten in keinem der genannten Organ- bzw. Hormonsysteme nennenswerte Unterschiede zur Wirkung von Östradiol. Die kontinuierliche Verabreichung zeigte keine bedeutenden Unterschiede zur zeitversetzten Kombination. Verglichen mit der sham-ovx Referenzgruppe präsentierten sich die Futteraufnahme, das Körpergewicht und das Hormonsystem (außer Östradiol) im physiologischen Bereich. Der Serumöstradiolwert, die uterine Schichtdicke des Myometriums und Epithels sowie die vaginale Epitheldicke wiesen supraphysiologische Werte auf. Die gewonnenen Resultate widersprechen somit der Gustafsson schen Yin-Yang-Theorie , nach welcher es durch die Stimulation des Östrogenrezeptors β zu einer hemmenden oder modulierenden Antwort der östrogenen Wirkung von Östradiol und dem selektiven ERα-Agonisten kommen sollte.

Submitted by Bianca Ribeiro De Souza null (mione_bi@msn.com) on 2017-09-18T05:28:24Z No. of bitstreams: 1 Dissertação (Final).pdf: 4000625 bytes, checksum: 7fde4629bfd1677d4c0087a9ad24c0ba (MD5) / Approved for entry into archive by Monique Sasaki (sayumi_sasaki@hotmail.com) on 2017-09-19T19:10:47Z (GMT) No. of bitstreams: 1 souza_br_me_assis.pdf: 4000625 bytes, checksum: 7fde4629bfd1677d4c0087a9ad24c0ba (MD5) / Made available in DSpace on 2017-09-19T19:10:47Z (GMT). No. of bitstreams: 1 souza_br_me_assis.pdf: 4000625 bytes, checksum: 7fde4629bfd1677d4c0087a9ad24c0ba (MD5) Previous issue date: 2017-08-04 / Os esteroides anabólicos androgênicos são prescritos para o tratamento de várias doenças, porém apresentam efeitos colaterais mesmo em dosagens terapêuticas. Entre eles, destaca-se o decanoato de nandrolona (DN), o qual age sobre receptores de andrógenos (AR) e estrógenos (ERα e ERβ). Paralelamente, a melatonina (MLT) tem despertado a atenção na área da saúde devido às suas propriedades antioxidantes e profiláticas, com o intuito de reduzir ou suprimir os efeitos colaterais promovidos por fármacos. Então, o presente estudo teve por objetivo avaliar o ciclo estral, a estrutura histológica e a imunomarcação para AR, ERα e ERβ em ovários de ratas androgenizadas submetidas ao tratamento com MLT. Ratas Wistar (n = 8/grupo) receberam óleo mineral (Controle), DN (7,5 mg/kg; via subcutânea, 15 dias) e o tratamento com MLT (10 mg/kg; via intraperitoneal, 7 dias) isoladamente, previamente ou concomitantemente ao esteroide. O ciclo estral foi monitorado. Os ovários foram coletados e preparados para a avaliação do tecido. Nas ratas androgenizadas, a MLT recuperou o peso e o tecido ovariano, mas não restabeleceu o ciclo estral. O número e área dos corpos lúteos dos animais que receberam MLT, previamente ou concomitantemente ao DN, foram similares ao controle, e apenas o tratamento prévio restabeleceu a quantidade de folículos saudáveis e atrésicos. Nos folículos, a MLT promoveu uma fraca expressão do ERα e ERβ, e nos corpos lúteos inibiu a diminuição na expressão de ERβ induzido pelo DN. O tratamento prévio com MLT atenuou o aumento na expressão do AR promovido pelo DN em folículos atrésicos e corpos lúteos. Em conclusão, a MLT apresentou efeito benéfico nos ovários androgenizados através da recuperação da foliculogênese e da luteogênese. O tratamento prévio com melatonina foi mais eficaz em relação ao tratamento concomitante. / Androgenic anabolic steroids are prescribed as treatment to several diseases, however, they present side effects even in therapeutic dosages. Among them, we highlight the nandrolone decanoate (ND) which acts on androgen receptors (AR) and estrogen receptors (ERα e ERβ). At the same time, melatonin (MLT) has raised attention in health area due to its antioxidant and prophylactic properties intending reduction or surpassing side effects caused by medicine. Thus, the present study aimed assess the estrous cycle, histological structure and AR, ERα and ERβ immunolocalization in androgenized rats ovaries undergone treatment with MLT. Wistar rats (n= 8/group) received mineral oil (Control), ND (7,5 mg/kg; subcutaneously, 15 days) and treatment with MLT (10 mg/kg; intraperitoneally, 7 days) singly, previously or concomitantly to steroid. Estrous cycle was monitored. The ovaries were collected and prepared for tissue assessment. In androgenized rats, MLT recovered weight and ovarian tissue, but it did not reestablish the estrous cycle. The number and area of corpus luteum of animals which received MLT, previously or concomitantly to ND, were similar to control, and only previous treatment reestablished the quantity of healthy and atretic follicles. In follicles, MLT promoted a weak expression of the ERα and ERβ, and in corpora lutea, it inhibited the decrease in the ERβ expression induced by ND. Previous treatment with MLT mitigated the increase in AR expression promoted by ND in atretic follicles and corporea lutea. In conclusion, melatonin presented a beneficial effect on the androgenized ovaries through the recovery of the folliculogenesis and luteogenesis. The previous treatment was the most effective.

Depuis bon nombre d’années déjà, la question ne se pose plus ; l’utilisation des pesticides en agriculture est nécessaire puisque sans ces derniers les chances que les terres soient ravagées par les insectes, champignons ou petits rongeurs représenteraient un trop grand risque pour les agriculteurs. Cependant, cette utilisation massive de pesticides en agriculture apporte son lot de questionnements et d’inquiétudes face aux effets néfastes qu’ils pourraient avoir tant sur les humains que sur la faune et la flore. Bien que tous les pesticides utilisés au Canada soient homologués par Santé Canada, et sont donc jugés comme ne représentant pas de risques élevés ni pour l’environnement ni les humains, nul ne connait les effets d’un mélange de pesticides sur nos cellules, notre organisme. Ce projet de recherche vise donc à évaluer les effets d’un mélange de pesticides composé de cinq ingrédients actifs communément utilisés en agriculture sur les niveaux d’expression du gène CYP1A1, un gène cible du récepteur aux hydrocarbures d'aryle (AhR). Ce récepteur, bien qu’impliqué dans bon nombre d’autres réponses cellulaires, joue un rôle important dans la détoxification de l’organisme en activant la transcription de certains gènes dans la famille du cytochrome P450, dont le gène CYP1A1. Tel que mentionné précédemment, le but du présent projet de recherche est d’évaluer les effets d’un mélange composé d’au moins deux ingrédients actifs de pesticides sur l’activation de la voie de AhR. Les résultats du projet de recherche ont démontré que certaines combinaisons donnent lieu à une activation synergique de la voie AhR alors que d’autres donnent plutôt lieu à une activation additive. Dans le cas où la concentration des ingrédients actifs est élevée, on obtient plutôt un effet inhibiteur. N’est-ce pas paradoxal qu’à faibles doses, il y a un effet soit additif ou synergique alors qu’à de hautes concentrations, l’effet est plutôt inhibiteur ? Il ne faut alors pas croire que de fortes doses de pesticides sont bénéfiques puisque les effets sur les niveaux d’expression des gènes cibles de AhR ne signifient pas qu’il en sera de même pour les tous les autres gènes. Les résultats ont également démontré qu’en présence d’œstrogène, les ingrédients actifs seuls ou en combinaison ont le même effet que le 2,3,7,8-Tétrachlorodibenzo-para-dioxine (TCDD) sur l’interaction croisée entre AhR et le récepteur aux œstrogènes ; l’expression du gène CYP1A1 est réprimée alors que l’expression de CYP1B1 demeure inchangée. Maintenant qu’on comprend bien les effets que peuvent avoir une combinaison d’ingrédients actifs de pesticides sur l’activation AhR, il ne reste plus qu’à comprendre pourquoi certains mélanges donnent lieu à une activation synergique et d’autres additive. Une question bien simple, mais à laquelle il est si difficile de répondre.

Obesity is a rapidly growing epidemic. It is associated with preventable chronic disease and vast healthcare cost in the United States (about 200 billion per year). Therefore, dissecting pathogenic mechanisms of obesity would provide effective strategies to prevent its development and reduce related cost. Obesity is characterized by excessive expansion of white adipose tissue (WAT). Autophagy, a cellular self-digestive process, is associated with WAT expansion and may be a promising target for combating obesity. Both hormone signaling (e.g., ERα) and energy sensing factors (e.g., Sirt1) control metabolism and prevent adiposity, and in which they have been shown to play collaborate roles. However, how autophagy is involved in ERα and Sirt1's inhibitory roles on adiposity is unknown. These questions have been addressed in my dissertation studies. To address this fundamental questions, I have established a method to monitor autophagy flux during adipocyte differentiation, which better reflected the dynamic process of autophagy. Compared with preadipocytes, autophagy flux activity was increased in mature adipocytes after differentiation. And then, my thesis project has addressed three main questions. Firstly, the gender difference in visceral fat distribution (Males have higher deposit of visceral fat than females) is controlled by an estradiol (E2)-autophagy axis. In C57BL/6J and wild type control mice, a higher visceral fat mass was detected in the males than in the females, which was associated with lower expression of estrogen receptor  (ER) and more active autophagy in males vs. females. ER knockout normalized this difference. Mechanistically, E2-ER- mTOR-ULK1-autophagy signaling contributed to the gender difference in visceral fat distribution. Secondly, in vitro and in vivo studies demonstrated that Sirt1 suppressed autophagy and reduced adipogenesis and adiposity via inducing mTOR-ULK1 signaling. Specific activation and overexpression of Sirt1 induced mTOR-ULK1 signaling to suppress autophagy and adipogenesis. And knockdown of Sirt1 exhibited opposite effects. The first and second studies revealed that ER and Sirt1 acted on mTOR-ULK1 signaling pathway, underlying the importance of their interaction in inhibiting autophagy and adipogenesis. As such, the third study was conducted and it unraveled that ER acted as upstream of Sirt1, possibly through its direct binding to Sirt1 promoter. Specifically, E2 signaling suppressed autophagy and adipogenesis. But when Sirt1 was knockdown, the effects of E2 on autophagy and adipogenesis were abolished. Taken together, my dissertation project underscores the importance for future research to consider gender difference and how E2-ER-autophagy axis contributes to this difference in other metabolic diseases. Also, the unraveled interaction between ERα and Sirt1 might lead to new therapeutic approach to adiposity and metabolic dysfunction in post-menopausal women or individuals with abnormal estrogen secretion. For example, dietary intervention or exercise challenge to activate Sirt1 may partially compensate estrogen deficiency. / Doctor of Philosophy / Obesity is a rapidly growing epidemic, which is associated with chronic disease and vast healthcare cost in the United States. Understanding the pathogenic mechanism of obesity is of critical importance. Recent studies have implicated autophagy, a cellular self-digestive process, in WAT development and expansion. It was also shown that hormone (e.g., via estrogen receptor ERα) and energy (e.g., via Sirt1) signaling control metabolism and adiposity. However, it is unclear whether and how autophagy interacts with ERα and Sirt1 in the regulation of adiposity. My dissertation project unraveled the mechanism of how hormone signaling (e.g., ERα) and energy sensing factors (e.g., Sirt1) interacted with autophagy to control adipogenesis and adiposity. My thesis project has addressed three main questions. Firstly, the gender difference in visceral fat distribution (Males have higher deposit of visceral fat than females) is controlled by an estradiol (E2)-autophagy axis, ER knockout normalized this difference. Mechanistically, E2- ER- mTOR-ULK1-autophagy signaling contributed to the gender difference in visceral fat distribution. Secondly, in vitro and in vivo studies demonstrated that Sirt1 induced mTOR-ULK1 signaling, suppressed autophagy and reduced adipogenesis and adiposity (ER similar effects). As such, the third study was conducted and it unraveled that ER acted as upstream of Sirt1, possibly through its direct binding to Sirt1 promoter. Taken together, my dissertation study has explored how hormone signaling (ER) and energy signaling (Sirt1) interact with autophagy to control adipogenesis and adiposity individually and collaboratively, which may provide new therapeutical approach to control obesity.

Stroke is a common and multifactorial disease influenced by genetic and environmental risk factors. It is a highly heterogeneous entity consisting of two main types, ischemic (80%) and hemorrhagic (20%) stroke. The most common form of hemorrhagic stroke is intracerebral hemorrhage (ICH). Ischemic stroke mainly results from thrombotic or embolic events, while ICH is caused by the rupture of an artery in the brain. The mean age of first-ever stroke is 75 years (73 vs. 78 years, for men and women, respectively) and the age-specific stroke incidence is higher for men as compared to women, suggesting that hormonal factors confer protection. A large body of experimental and observational studies shows that estrogens exert beneficial effects in the cardiovascular system. However, large, recent, clinical randomized trials have failed to demonstrate a lower risk of stroke with hormone replacement therapy (HRT) in elderly postmenopausal women. It is possible that HRT may only protect a subgroup of women. Here, genetic predisposition might be involved. Stroke incidence is 50% higher in northern compared to southern Sweden, suggesting a genetic predisposition in this population. This relatively homogeneous population displays founder effects, making it well suited for genetic studies. Since 1985, the MONICA and VIP projects have conducted large-scale cardiovascular health surveys in this population. Information about conventional stroke risk determinants and also DNA have been collected, and two prospective, nested case-referent cohorts (113 cases and 226 controls; 275 cases and 549 controls) have been sampled. To investigate whether genes of the estrogen signaling system may be important in stroke development, we performed genetic association studies, including specific functional single nucleotide polymorphisms in the genes for estrogen receptor alpha (ERα, ESR1), and its target genes osteoprotegerin (OPG, TNFRS11B) and interleukin-6 (IL-6, IL6). We found a significant association between the common c.454-397T/T genotype in ESR1 and ICH, remaining after adjustments for conventional stroke risk factors. The c.454-397T/T genotype also associated with increased systolic (SBP) and diastolic blood pressure (DBP). The combination of c.454- 397T/T and either hypertension, increased SBP, or increased DBP boosted this association substantially and significant synergistic effects on ICH risk between this genotype and increased blood pressure were demonstrated. In a second study, we found a similar association between the common OPG-1181C/C genotype and ICH. Cognitive impairments, including spatial memory and learning deficiencies, are common after stroke. Estrogens improve cognitive functions, including memory and learning processes, in postmenopausal women and ovariectomized rodents. Post-ischemic housing of rats in an enriched environment (EE) improves recovery of spatial memory and learning impairments. Both estrogen and EE induce neuroplasticity in the hippocampus. We hypothesized that 17β- estradiol combined with EE would accelerate recovery after experimental focal brain ischemia in ovariectomized rats and that such improvements could be related to expression of nerve growth factor-induced gene A (NGFI-A) in the hippocampus. Five to six weeks after middle cerebral artery occlusion, 17β-estradiol–treated rats housed in an EE showed significant improvements in cognitive function (i.e., shorter latency and path in the Morris water maze task) and significantly higher NGFI-A mRNA expression in bilateral cornu ammonis 1 (CA1) and ipsilateral dentate gyrus (DG) compared to placebo-treated animals in EE. In conclusion, we present evidence for the association between polymorphic variants in the ESR1 and TNFRS11B genes and ICH and show that 17β-estradiol in combination with EE accelerates cognitive functions in a rat stroke model, putatively through upregulation of NGFI-A in hippocampal subregions. These findings may contribute to an increased understanding of the underlying genetic etiology of ICH and may be informative for the primary prevention of this disease. They also provide hope for 17β-estradiol combined with early environmental enrichment as a novel therapeutic option following ischemic stroke.

La croissance de deux tiers des tumeurs mammaires dépend des œstrogènes. Le réseau de gènes responsable de propager les signaux prolifératifs des œstrogènes est encore mal connu. Des micropuces d’ADN de cellules de carcinome mammaire MCF7 traitées à l’œstradiol (E2) avec ou sans l’inhibiteur de synthèse protéique cycloheximide (CHX) ont permis d’identifier de nombreux gènes cibles primaires et secondaires. La séquence des promoteurs des gènes cibles a été criblée à l’aide d’une banque de 300 matrices modélisant les sites reconnus par divers facteurs de transcription. Les éléments de réponse aux œstrogènes (ERE) sont enrichis dans les promoteurs des gènes primaires. Les sites E2F sont enrichis dans les promoteurs des gènes cible secondaires. Un enrichissement similaire a été observé avec les régions liées par ERα et E2F1 en ChIP-on-chip pour chacune des catégories de gènes. La croissance des cellules de carcinome mammaire est inhibée par des traitements à l’acide rétinoïque (RA). L’analyse de micropuces d’ADN de MCF7 traitées avec RA a permis d’identifier de nombreux gènes cibles potentiels. Un enrichissement d’éléments de réponse à l’acide rétinoïque (RARE) est observable dans les promoteurs de ces gènes après avoir exclus les RARE se trouvant à l’intérieur d’éléments transposables. Des RARE présents dans des éléments transposables spécifiques aux primates sont aussi fixés in vivo dans les promoteurs de cibles connues de RA : BTG2, CASP9 et GPRC5A. Certains gènes cibles de RA dans les MCF7 sont aussi des cibles de E2, suggérant que le contrôle que ces molécules exercent sur la prolifération est en partie attribuable à des effets opposés sur un ensemble commun de gènes. / Two thirds of breast tumours depend on estrogens for their growth. The network of genes mediating the proliferative effect of estrogens is not fully characterized. Putative primary and secondary estrogen target genes were identified with microarray analysis of MCF7 breast cancer cells treated with estradiol (E2) in presence or absence of the protein synthesis inhibitor cycloheximide (CHX). The promoters of the target genes were screened for transcription factor binding sites with a collection of 300 matrix based DNA-binding profiles. Estrogen response elements (EREs) were enriched in the promoters of primary target genes. E2F binding sites were enriched in the promoters of secondary target genes. Similar enrichment was also observed in regions bounds by ERα and E2F1 in ChIP-on-chip experiments for each set of target genes. Retinoic acid (RA) treatment of mammary carcinoma cells inhibits their growth. Putative target genes were identified through microarray analysis of MCF7 cells treated with RA. Enrichment of retinoic acid response elements (RARE) was observed in their promoters after removing the elements found within transposable elements. Although transposable elements mask the enrichment, RARE within primate specific transposable elements are bound in vivo by retinoic acid receptors in the promoters of known target genes BTG2, CASP9 and GPRC5A. Some of the RA target genes in MCF7 cells are also target genes of E2 suggesting that these two molecules exert their effects on cell proliferation in part by opposite action on a common set of genes.