Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Estrogen receptors (ER) α and β are found in both women and men in many tissues, where they have different functions, including having roles in cell proliferation and differentiation of the reproductive tract. In addition to estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and modulate their activities. Among these compounds, phytoestrogens such as isoflavones, which are found in plants, are promising therapeutics for several pathologies. Glyceollins are second metabolites of isoflavones that are mainly produced in soybean in response to an elicitor. They have potentially therapeutic actions in breast cancer by reducing the proliferation of cancer cells. However, the molecular mechanisms driving these effects remain elusive. METHODS: First, to determine the proliferative or anti-proliferative effects of glyceollins, in vivo and in vitro approaches were used. The length of epithelial duct in mammary gland as well as uterotrophy after treatment by E2 and glyceollins and their effect on proliferation of different breast cell line were assessed. Secondly, the ability of glyceollin to activate ER was assessed by luciferase assay. Finally, to unravel molecular mechanisms involved by glyceollins, transcriptomic analysis was performed on MCF-7 breast cancer cells. RESULTS: In this study, we show that synthetic versions of glyceollin I and II exert anti-proliferative effects in vivo in mouse mammary glands and in vitro in different ER-positive and ER-negative breast cell lines. Using transcriptomic analysis, we produce for the first time an integrated view of gene regulation in response to glyceollins and reveal that these phytochemicals act through at least two major pathways. One pathway involving FOXM1 and ERα is directly linked to proliferation. The other involves the HIF family and reveals that stress is a potential factor in the anti-proliferative effects of glyceollins due to its role in increasing the expression of REDD1, an mTORC1 inhibitor. CONCLUSION: Overall, our study clearly shows that glyceollins exert anti-proliferative effects by reducing the expression of genes encoding cell cycle and mitosis-associated factors and biomarkers overexpressed in cancers and by increasing the expression of growth arrest-related genes. These results reinforce the therapeutic potential of glyceollins for breast cancer.
ISSN: 1478-811X

hal-01560288
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560288
DOI : 10.1186/s12964-017-0182-1
PUBMED : 28666461

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
This study aimed to compare the relative survival of patients with invasive breast cancer between women from French Guiana (a French territory in South America) and metropolitan France. No study hadever compared survival of breast cancer on the basis of immigrant status in France. Our study underlined that access to care for migrants is challenging whichwgenerates health inequalities. Background The prognosis of breast cancer in French Guiana is worse than in France with 23 deaths per 100 incident cases against 17 per 100 in metropolitan France. This study aimed to compare relative survival of patients with invasive breast cancer (IBC) between women from French Guiana and metropolitan France and to determine risk factors influencing breast cancer survival in French Guiana.Materials and methods Data were collected from the Cancer registry of French Guiana. We comparedthe relative survival of women with IBC between French Guiana and metropolitan France. We used Cox's proportional hazard regression to evaluate the effect of prognostic factors on cancer-specific mortality in French Guiana. Results We included all 269 cases of IBC in women diagnosed in French Guiana between 2003 and 2009. The overall 5-year relative survival rate of patients with IBC was 79% in French Guiana and 86% in metropolitan France. The place of birth (foreign country versus French territory), the tumor stage at the time of diagnosis, the mode of diagnosis (symptoms versus screening), the presence of hormone receptors in the tumor and the histologic type were the variables associated with survival differences. None of the other study variables were significantly associated with prognosis. Conclusion Access to care for migrants is challenging,which leads to health inequalities. Early detection through prevention programs is crucial to increaseIBC survival notably for foreign-born patients.
ISSN: 1526-8209

hal-01288657
https://hal.archives-ouvertes.fr/hal-01288657
https://hal.archives-ouvertes.fr/hal-01288657/document
https://hal.archives-ouvertes.fr/hal-01288657/file/2016%2C%20Roue%20-%20Predictive%20factors%20of%20the%20survival%20of%20women%20with%20invasive%20breast%20cancer%20in%20French%20Guiana.pdf

Éditeur(s) : HAL CCSD
Résumé : International audience
Purpose: Social inequalities in cancer incidence and mortality have been reported in France, but no data are available for the French overseas territories. Our objective was to explore the association between cancer incidence and the socioeconomic level of the residence area in the French West Indies. Methods: Cancer incidence data were obtained from the cancer registries of Guadeloupe and Martinique (2009–2010). To assess socioeconomic status, we developed a specific index of social deprivation from census data at a small area level. We used Bayesian methods to evaluate the association between cancer incidence and the deprivation index, for all cancers combined and for the major cancer sites. Results: There was no clear association between area‐based deprivation and the incidence of all cancers combined. In men, higher area deprivation was associated with a higher incidence of prostate cancer (relative risk (RR) 1.25, 95% credible interval (CI) 1.04–1.49; RR 1.08, CI 0.91–1.29 in the categories of intermediate and high deprivation, respectively, compared to low deprivation), but was not associated with respiratory cancer. Women living in the most deprived areas had a higher incidence of stomach (RR 1.77, CI 1.12–2.89), breast (RR 1.15, CI 0.90–1.45), and cervical (RR 1.13, CI 0.63–2.01) cancers and a lower incidence of respiratory cancer (RR 0.65, CI 0.38–1.11). Conclusion: These first results in the French West Indies suggest specific patterns for some cancer sites that need to be further investigated. © 2017, Springer International Publishing AG.
Cancer Causes and Control

hal-01671494
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01671494
DOI : 10.1007/s10552-017-0946-3
PUBMED : 28849411

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
Objective Large-scale prospective studies do not support an association between neuroticism and extroversion with cancer incidence. However, research on other personality constructs is inconclusive. This longitudinal study examined the associations between four personality measures, Type 1, "suppressed emotional expression"; Type 5, "rational/antiemotional"; hostility; and Type A with cancer incidence. Methods Personality measures were available for 13,768 members in the GAZEL cohort study (baseline assessment in 1993). Follow-up for diagnoses of primary cancers was obtained from January 1, 1994 to December 31, 2009. Associations between personality and cancer incidence were evaluated using Cox proportional hazards analyses and adjusted for potential confounders. Results During a median follow-up of 16.0 years (range, 9 days-16 years), 1139 participants were diagnosed as having a primary cancer. The mean duration between baseline and cancer diagnosis was 9.3 years. Type 1 personality was associated with a decreased risk of breast cancer (hazard ratio per standard deviation = 0.81, 95% confidence interval = 0.68-0.97, p = .02). Type 5 personality was not associated with prostate, breast, colorectal, or smoking-related cancers, but was associated with other cancers (hazard ratio per standard deviation = 1.17, 95% confidence interval = 1.04-1.31, p = .01). Hostility was associated with an increased risk of smoking-related cancers, which was explained by smoking habits, and Type A was not associated with any of the cancer endpoints. Conclusions Several personality measures were prospectively associated with the incidence of selected cancers. These links may warrant further epidemiological studies and investigations about potential biobehavioral mechanisms.
ISSN: 0033-3174

inserm-00813178
http://www.hal.inserm.fr/inserm-00813178
http://www.hal.inserm.fr/inserm-00813178/document
http://www.hal.inserm.fr/inserm-00813178/file/PersonalityCancer_Lemogne_Psychosom_Med_2013.pdf
http://www.hal.inserm.fr/inserm-00813178/file/inserm-00813178_edited.pdf

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Estrogen receptor alpha (ERα) is generally considered to be a good prognostic marker because almost 70% of ERα-positive tumors respond to anti-hormone therapies. Unfortunately, during cancer progression, mammary tumors can escape from estrogen control, resulting in resistance to treatment. In this study, we demonstrate that activation of the actin/megakaryoblastic leukemia 1 (MKL1) signaling pathway promotes the hormonal escape of estrogen-sensitive breast cancer cell lines. The actin/MKL1 signaling pathway is silenced in differentiated ERα-positive breast cancer MCF-7 and T47D cell lines and active in ERα-negative HMT-3522 T4-2 and MDA-MB-231 breast cancer cells, which have undergone epithelial-mesenchymal transition. We showed that MKL1 activation in MCF-7 cells, either by modulating actin dynamics or using MKL1 mutants, down-regulates ERα expression and abolishes E2-dependent cell growth. Interestingly, the constitutively active form of MKL1 represses PR and HER2 expression in these cells and increases the expression of HB-EGF, TGFβ, and amphiregulin growth factors in an E2-independent manner. The resulting expression profile (ER-, PR-, HER2-) typically corresponds to the triple-negative breast cancer expression profile.
ISSN: 0303-7207

hal-01061363
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01061363/file/Activationsur the_MKL1actin_Kerdivel_et_al._text_Figures.pdf
DOI : 10.1016/j.mce.2014.03.009

Résumé : L'objectif du registre des cancers de Guyane est de collecter l ensemble des tumeurs invasives et/ou in situ survenues depuis le 1er janvier 2003 chez des patients vivant en Guyane, quels que soient la localisation de la tumeur, le lieu de diagnostic et de traitement. Cette thèse a pour but de décrire la population atteinte d un cancer afin d améliorer les connaissances sur cette maladie et ainsi de permettre aux actions de santé publique d être plus efficaces.De 2003 à 2009, le taux d incidence des cancers standardisé sur l âge était, dans les deux sexes, 30% inférieur en Guyane par rapport à la France métropolitaine et n était pas différent de celui d Amérique du Sud.Nous avons comparé l incidence, la mortalité et la survie relative des patientes atteintes d un cancer invasif du sein (CIS) et des patientes atteintes d un cancer invasif du col de l utérus (CIC) entre la Guyane et la métropole.Le ratio incidence/mortalité indiquait que les cancers du sein étaient de plus mauvais pronostic en Guyane par rapport à la métropole.La survie relative des femmes atteintes d un CIS était inférieure en Guyane par rapport à la France métropolitaine.En Guyane, le taux standardisé d incidence du cancer du col de l utérus était 4 fois plus élevé qu en métropole. Les femmes vivant dans l intérieur de la Guyane semblaient être diagnostiquées à un stade plus tardif et plus souvent sur symptômes que les femmes du littoral. L accès aux soins des migrants est un challenge et une source d inégalité de santé. La détection précoce des cancers à travers des programmes de prévention est cruciale pour améliorer la survie par cancer et notamment chez les patients étrangers.
The objective of the cancer registry of French Guiana is to compile all patients living in French Guiana with malignant invasive pathology and/or in situ lesions starting January 1st 2003 in persons living in French Guiana, whatever the tumoral location and the place of diagnosis and care. This study aimed to describe the population with invasive cancer to improve the knowledge about this disease in order to target public health interventions more effectively.The age standardised incidence rate was 30% times lower than in France in both sexes and the same than in South America.We compared incidence and relative survival of patients with invasive breast cancer (IBC) and patients with invasive cervical cancer (ICC) between women from French Guiana and metropolitan France.The ratio between incidence and mortality showed that the prognosis of IBC in French Guiana was worse than in metropolitan France.The relative survival rate among women with IBC in French Guiana was lower than among women in metropolitan France.In French Guiana, the age-standardized incidence rate of cervical cancer was four times higher than in France. Women living in remote areas seemed to be diagnosed later and more often following symptoms.Access to care for migrants is challenging and sustains health inequalities. Early detection through prevention programs is crucial for increasing cancer survival notably for foreign-born patients. Further studies with more patients and other variables could improve the knowledge about these diseases

http://www.theses.fr/2014AGUY0743/document

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND: The insecticide chlordecone was extensively used in the French West Indies to control banana root borer. Its persistence in soils has led to the widespread pollution of the environment, and human beings are still exposed to this chemical. Chlordecone has been shown to impair neurological and behavioural functions in rodents when exposed gestationally or neonatally. OBJECTIVES: The aim of the study was to evaluate the impact of prenatal and postnatal exposure to chlordecone on the cognitive, visual, and motor development of 7-month-old infants from Guadeloupe. METHODS: Infants were tested at 7 months (n=153). Visual recognition memory and processing speed were assessed with the Fagan Tests of Infant Intelligence (FTII), visual acuity with the Teller Acuity Card, and fine motor development with the Brunet-Lezine. Samples of cord blood and breast milk at 3 months (n=88) were analyzed for chlordecone concentrations. Postnatal exposure was determined through breast feeding and frequency of contaminated food consumption by the infants. RESULTS: Cord chlordecone concentrations in tertiles were associated with reduced novelty preference on the FTII in the highly exposed group (β=-0.19, p=0.02). Postnatal exposure through contaminated food consumption was marginally related to reduced novelty preference (β=-0.14, p=0.07), and longer processing speed (β=0.16, p=0.07). Detectable levels of chlordecone in cord blood were associated with higher risk of obtaining low scores on the fine motor development scale (OR=1.25, p<0.01). CONCLUSION: These results suggest that pre- and postnatal low chronic exposure to chlordecone is associated with negative effects on cognitive and motor development during infancy.
ISSN: 0013-9351

hal-00875939
https://hal.archives-ouvertes.fr/hal-00875939
DOI : 10.1016/j.envres.2012.07.006
PUBMED : 22910562

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Socioeconomic inequalities in cancer mortality have been observed in different European countries and the US until the end of the 1990s, with changes over time in the magnitude of these inequalities and contrasted situations between countries. The aim of this study is to estimate relative and absolute educational differences in cancer mortality in France between 1999 and 2007, and to compare these inequalities with those reported during the 1990s. METHODS: Data from a representative sample including 1% of the French population were analysed. Educational differences among people aged 30--74 were quantified with hazard ratios and relative indices of inequality (RII) computed using Cox regression models as well as mortality rate difference and population attributable fraction. RESULTS: In the period 1999--2007, large relative inequalities were found among men for total cancer and smoking and/or alcohol related cancers mortality (lung, head and neck, oesophagus). Among women, educational differences were reported for total cancer, head and neck and uterus cancer mortality. No association was found between education and breast cancer mortality. Slight educational differences in colorectal cancer mortality were observed in men and women. For most frequent cancers, no change was observed in the magnitude of relative inequalities in mortality between the 1990s and the 2000s, although the RII for lung cancer increased both in men and women. Among women, a large increase in absolute inequalities in mortality was observed for all cancers combined, lung, head and neck and colorectal cancer. In contrast, among men, absolute inequalities in mortality decreased for all smoking and/or alcohol related cancers. CONCLUSION: Although social inequalities in cancer mortality are still high among men, an encouraging trend is observed. Among women though, the situation regarding social inequalities is less favourable, mainly due to a health improvement limited to higher educated women. These inequalities may be expected to further increase in future years.
ISSN: 1471-2458

inserm-00868759
http://www.hal.inserm.fr/inserm-00868759
http://www.hal.inserm.fr/inserm-00868759/document
http://www.hal.inserm.fr/inserm-00868759/file/1471-2458-13-823.pdf
DOI : 10.1186/1471-2458-13-823

Éditeur(s) : HAL CCSD Lippincott, Williams & Wilkins
Résumé : International audience
The aim of this study was to investigate the role of socioeconomic and healthcare use characteristics in the participation in breast, cervical and colorectal cancer screening in the French West Indies. We used data from a national health survey conducted in 2014 in Martinique (n=2026) and Guadeloupe (n=2028). Logistic regressions adjusted for various sociodemographic and morbidity variables were performed. The following determinants were investigated: having hot water at home, having received income support for low-income individuals during the last year, educational level, occupational class, complementary health insurance, healthcare renouncement and visit to the general practitioner (GP) during the last year. Multiple imputations were performed to account for missing values. We observed the following cancer screening rates: 78.1% for cervical cancer, 81.5% for breast cancer and 59.5% (women) and 50.8% (men) for colorectal cancer. Higher cervical cancer screening participation was reported among women with qualified occupation and having visited the GP during the last year and lower participation among women who never worked. Higher screening participation was reported among participants having hot water at home and having visited the GP during the last year for breast and colorectal (men and women) cancer. Unexpectedly, a lower colorectal cancer screening participation was found among women with qualified occupation. We observed social inequalities in participation in cancer screening in the French West Indies, which stresses the need to continue efforts to increase screening rates in this population.
ISSN: 0959-8278

hal-01525894
http://hal.upmc.fr/hal-01525894
http://hal.upmc.fr/hal-01525894/document
http://hal.upmc.fr/hal-01525894/file/Menvielle_2016_Socioeconomic_and.pdf
DOI : 10.1097/CEJ.0000000000000329

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BackgroundTo 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.MethodsUsing 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.ResultsERα46 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.ConclusionsWe 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.
ISSN: 1465-5411

inserm-01412032
http://www.hal.inserm.fr/inserm-01412032
http://www.hal.inserm.fr/inserm-01412032/document
http://www.hal.inserm.fr/inserm-01412032/file/13058_2016_Article_780.pdf
DOI : 10.1186/s13058-016-0780-7

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Background: Mass breast cancer screening is offered to French women between the ages of 50 and 74. In the French overseas department of Guadeloupe, where the population is of mostly African ancestry, a low age at diagnosis of breast cancer has been reported, as for African-Americans. This raises the question of whether breast cancer is more aggressive in the age group preceding that eligible for mass screening (4049) in Guadeloupe. Methods: We compared the tumor-related prognostic factors, first line therapy and overall survival rates of breast cancer cases diagnosed between the 40-49 and 50-74 age groups, based on reports of the cancer registry of Guadeloupe for the period 2008-2013. Results: The characteristics studied, risk of death after breast cancer (HR 0.84 [95% CI: 0.58-1.22] and overall survival, did not differ significantly between the two groups, except for higher tumor size (28.8 vs 24.0; p = 0.004) in the younger group. Conclusion: These results do not show a pattern of more aggressive breast cancer in the age group preceding that eligible for mass screening in Guadeloupe. (C) 2017 Elsevier Ltd. All rights reserved.
ISSN: 1877-7821

hal-01659244
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01659244
DOI : 10.1016/j.canep.2017.08.004
PUBMED : 29120835

Éditeur(s) : HAL CCSD Endocrine Society
Résumé : International audience
Transcriptional regulation by the estrogen receptor-alpha(ER) has been investigated mainly in breast cancer cell lines, but estrogens such as 17 beta-estradiol (E2) exert numerous extrareproductive effects, particularly in the liver, where E2 exhibits both protective metabolic and deleterious thrombotic actions. To analyze the direct and early transcriptional effects of estrogens in the liver, we determined the E2-sensitive transcriptome and ER cistrome in mice after acute administration of E2 or placebo. These analyses revealed the early induction of genes involved in lipid metabolism, which fits with the crucial role of ER in the prevention of liver steatosis. Characterization of the chromatin state of ER binding sites (BSs) in mice expressing or not ER demonstrated that ER is not required per se for the establishment and/or maintenance of chromatin modifications at the majority of its BSs. This is presumably a consequence of a strong overlap between ER and hepatocyte nuclear factor 4 alpha BSs. In contrast, 40% of the BSs of the pioneer factor forkhead box protein a (Foxa2) were dependent upon ER expression, and ER expression also affected the distribution of nucleosomes harboring dimethylated lysine 4 of Histone H3 around Foxa2 BSs. We finally show that, in addition to a network of liver-specific transcription factors including CCAAT/enhancer-binding protein and hepatocyte nuclear factor 4 alpha, ER might be required for proper Foxa2 function in this tissue.
ISSN: 0888-8809

hal-01357623
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01357623/file/Changes%20in%20gene%20expression%201%20and%20Estrogen%20Receptor_accepted.pdf
DOI : 10.1210/me.2015-1311

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.
ISSN: 0041-008X

hal-01558816
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01558816/file/Lecomte%20et%20al.%20-%20Assessment%20of%20the%20potential%20activity%20of%20major%20diet.pdf
DOI : 10.1016/j.taap.2017.04.005

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: The orphan receptors COUP-TF (chicken ovalbumin upstream promoter transcription factor) I and II are members of the nuclear receptor superfamily that play distinct and critical roles in vertebrate organogenesis. The involvement of COUP-TFs in cancer development has recently been suggested by several studies but remains poorly understood. METHODS: MCF-7 breast cancer cells overexpressing COUP-TFI and human breast tumors were used to investigate the role of COUP-TFI in the regulation of CXCL12/CXCR4 signaling axis in relation to cell growth and migration. We used Immunofluorescence, western-blot, RT-PCR, Formaldehyde-assisted Isolation of Regulatory Elements (FAIRE) assays, as well as cell proliferation and migration assays. RESULTS: Previously, we showed that COUP-TFI expression is enhanced in breast cancer compared to normal tissue. Here, we report that the CXCL12/CXCR4 signaling pathway, a crucial pathway in cell growth and migration, is an endogenous target of COUP-TFI in breast cancer cells. The overexpression of COUP-TFI in MCF-7 cells inhibits the expression of the chemokine CXCL12 and markedly enhances the expression of its receptor, CXCR4. Our results demonstrate that the modification of CXCL12/CXCR4 expression by COUP-TFI is mediated by the activation of epithelial growth factor (EGF) and the EGF receptor. Furthermore, we provide evidence that these effects of COUP-TFI increase the growth and motility of MCF-7 cells in response to CXCL12. Cell migration toward a CXCL12 gradient was inhibited by AMD3100, a specific antagonist of CXCR4, or in the presence of excess CXCL12 in the cell culture medium. The expression profiles of CXCR4, CXCR7, CXCL12, and COUP-TFI mRNA in 82 breast tumors and control non-tumor samples were measured using real-time PCR. CXCR4 expression was found to be significantly increased in the tumors and correlated with the tumor grade, whereas the expression of CXCL12 was significantly decreased in the tumors compared with the healthy samples. Significantly higher COUP-TFI mRNA expression was also detected in grade 1 tumors. CONCLUSIONS: Together, our mechanistic in vitro assays and in vivo results suggest that a reduction in chemokine CXCL12 expression, with an enhancement of CXCR4 expression, provoked by COUP-TFI, could be associated with an increase in the invasive potential of breast cancer cells.
ISSN: 1471-2407

hal-01024753
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01024753/file/1471-2407-14-407.pdf
DOI : 10.1186/1471-2407-14-407

Éditeur(s) : HAL CCSD
Résumé : International audience
Based on US national cancer registry data, age differences at breast cancer diagnosis have been reported between African-American women and European-American women. Such differences between populations of African and European ancestry have not been studied in other countries at a nationwide level. Here, we report and compare descriptive nationwide epidemiological indicators of invasive breast cancer for the populations of European ancestry living in the US and in mainland France and for women of African ancestry living in the US and in the French West Indies (Martinique and Guadeloupe). Based on the available data, we determined age frequency distributions, world age-standardized incidence, and the distribution of expected cases of breast cancer in a standard population of women by age. The age frequency distributions revealed that women of African ancestry were younger at diagnosis than women of European ancestry. By contrast, compared with the US regardless of ancestry and mainland France, the standardized incidences appeared lower, and the largest numbers of expected cases younger, in the French West Indies. The populations with African ancestry were not homogeneous in terms of epidemiologic indicators of age-related breast cancer. These descriptive findings suggest that populations of African ancestry cannot be considered uniform when determining whether it would be appropriate to decrease the age of entry into screening programs for breast cancer.
The Breast Journal

hal-01063922
https://hal.archives-ouvertes.fr/hal-01063922
DOI : 10.1111/tbj.12228
PUBMED : 24617611

Éditeur(s) : HAL CCSD John Libbey Eurotext
Résumé : International audience
The principal gynaecological cancers (breast, ovary, uterus, and cervix) account for over 40% of cancers found in women worldwide. However, large differences exist, in both their incidence and geographical distribution. The French West Indies, through their location, environment, socio-economic development, lifestyle, nutrition and the origins of their populations, constitute territories with a very particular character in the heart of the Caribbean. These characteristics have an impact on public health and can affect the incidence of tumours. We report for the first time the incidence of these major gynaecological cancers in Guadeloupe. Breast, ovary and uterine cancers have lower incidences in Guadeloupe than in mainland France. By contrast, cervical cancer is more frequent in Guadeloupe than in mainland France. The mortality rates associated with breast cancer, ovary and uterine cancer are also lower in Guadeloupe than in mainland France, whereas the opposite pattern is observed for cervical cancer. These observations may be accounted for in part by a difference in the prevalence of established or suspected risk factors for each of these types of cancer.
ISSN: 0007-4551

inserm-00504624
http://www.hal.inserm.fr/inserm-00504624
DOI : 10.1684/bdc.2008.0810
PUBMED : 19258222

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The increased expression of the Disintegrin and Metalloprotease ADAM12 has been associated with human cancers, however its role remain unclear. We have previously reported that ADAM12 expression is induced by the transforming growth factor, TGF-β and promotes TGF-β-dependent signaling through interaction with the type II receptor of TGF-β. Here we explore the implication of ADAM12 in TGF-β-mediated epithelial to mesenchymal transition (EMT), a key process in cancer progression. We show that ADAM12 expression is correlated with EMT markers in human breast cancer cell lines and biopsies. Using a non-malignant breast epithelial cell line (MCF10A), we demonstrate that TGF-β-induced EMT increases expression of the membrane-anchored ADAM12L long form. Importantly, ADAM12L overexpression in MCF10A is sufficient to induce loss of cell-cell contact, reorganization of actin cytoskeleton, up-regulation of EMT markers and chemoresistance. These effects are independent of the proteolytic activity but require the cytoplasmic tail and are specific of ADAM12L since overexpression of ADAM12S failed to induce similar changes. We further demonstrate that ADAM12L-dependent EMT is associated with increased phosphorylation of Smad3, Akt and ERK proteins. Conversely, inhibition of TGF-β receptors or ERK activities reverses ADAM12L-induced mesenchymal phenotype. Together our data demonstrate that ADAM12L is associated with EMT and contributes to TGF-β-dependent EMT by favoring both Smad-dependent and Smad-independent pathways
ISSN: 1932-6203

hal-01207281
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01207281
DOI : 10.1371/journal.pone.0139179
PUBMED : 26407179

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology
ISSN: 0022-2623

hal-01187307
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187307
DOI : 10.1021/acs.jmedchem.5b00991
PUBMED : 26237138

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.
ISSN: 1422-0067

hal-01560283
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560283
PUBMED : 28657580
DOI : 10.3390/ijms18071381

Éditeur(s) : HAL CCSD
Résumé : International audience
Background: Geographical disparities in breast cancer incidence and outcomes are reported worldwide. Women of African descent show lower incidence, higher mortality rates and earlier age of onset. We analyzed data from the cancer registry of Guadeloupe for the period 2008-2013. Methods: We describe breast cancer characteristics by molecular subtype, as well as estimated observed and net survival. We used Cox proportional hazard models to determine associations between cancer subtypes and death rate, adjusted for variables of interest. Results: Overall, 1275 cases were recorded with a mean age at diagnosis of 57(+/- 14) years. World standardized incidence and mortality were respectively 71.9/100,000 and 14.1/100,000 person-years. Age-specific incidence rates were comparable to European and US populations below the age of 45, and higher in Guadeloupean women aged between 45 and 55 years. Overall, 65.1% of patients were hormone receptor (HR)+ and 20.1% were HR-. Triple negative breast cancers (TNBC) accounted for 14% of all cases, and were more frequent in patients under 40 (21.6% vs. 13.4%, p = 0.02). Five-year net survival was 84.9% [81.4-88.6]. It was higher for HR+/Her2+ and HR+/Her2-subtypes, and lower for HR-/Her2+ and TNBC patients. Conclusion: We found high age-specific incidence rates of breast cancer in women aged 45 to 55 years, which warrants further investigation in our population. However, this population of mainly African descent had good overall survival rates, and data according to subtypes are consistent with those reported internationally. These results may suggest that poorer survival in other African descent populations may not be an inherent feature of the disease but may be amenable to improvement. (C) 2017 Elsevier Ltd. All rights reserved.
Cancer Epidemiology

hal-01519252
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01519252
DOI : 10.1016/j.canep.2017.01.004
PUBMED : 28119121