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¹ Unité INSERM 540, 60 rue de Navacelles, 34090 Montpellier, France
² Laboratoire de Biologie Cellulaire, Centre Hospitalier Universitaire de Montpellier, Hôpital Arnaud de Villeneuve, 271, Av G. Giraud, 34295 Montpellier, France

(Requests for offprints should be addressed to P Pujol, Service de Biologie Cellulaire, Hôpital Arnaud de Villeneuve, CHU, 271, Av G. Giraud, 34295 Montpellier, France; Email: p-pujol{at}chu-montpellier.fr)

	Abstract

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

 
The characterization of estrogen receptor beta (ERß) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERß expression in cancer as compared with benign tumors or normal tissues, whereas ER expression persists. The loss of ERß expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ER target genes by ERß or ERß-specific gene induction could explain that ERß has a differential effect on proliferation as compared with ER. ERß may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ER and ERß expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

	Introduction

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

 
It is well documented that the mitogenic actions of estrogens are critical in the etiology and progression of human breast and gynecologic cancers (Henderson et al. 1988, Pike et al. 1993). The promoting effect of estrogens was recently highlighted by the results of large prospective studies, showing that estradiol intake during menopause increased the risk of breast cancer (BC) (Nelson et al. 2002, Rossouw et al. 2002, Beral et al. 2003, Chlebowski et al. 2003). In ovarian cancer, although the question is still debated (Coughlin et al. 2000), several recent prospective studies have indicated a risk of ovarian cancer for women undergoing long-term estrogen replacement therapy (Rodriguez et al. 2001, Lacey et al. 2002, Anderson et al. 2003, Folsom et al. 2004). In contrast, estrogens appear to exert a protective effect on the risk of colon cancer (Rossouw et al. 2002).

The effects of estrogens are mediated by estrogen receptor (ER) and ERß, which are members of the nuclear steroid receptor superfamily. ER and ERß classically mediate their action by ligand-dependent binding to the estrogen-response element (ERE) of target genes, leading to their transcription regulation (Green et al. 1986, Kuiper et al. 1996, Mosselman et al. 1996, Tremblay et al. 1997). Both of these proteins have a high degree of homology in the DNA-binding domain (Mosselman et al. 1996), but differ considerably in the N-terminal domain and to a lesser extent in the ligand-binding domain (E domain) (Kuiper et al. 1996, Mosselman et al. 1996). These differences suggest that the two receptors could have distinct functions in terms of gene regulation and biologic responses and may contribute to the selective actions of 17-ß-estradiol (E2) in different target tissues (Gustafsson & Warner 2000).

Recently, various studies have shown decreased expression of ERß mRNA and protein (or an increased ER /ERß mRNA ratio) in tumor versus normal tissues in many cancers, including breast, ovary, colon and prostate (Brandenberger et al. 1998, Pujol et al. 1998, Foley et al. 2000, Rutherford et al. 2000, Campbell-Thompson et al. 2001, Roger et al. 2001, Fixemer et al. 2003). The ER/ERß gene expression ratio thus appears to increase during carcinogenesis, suggesting that ER- and ERß-specific pathways may have distinct roles in this process (Leygue et al. 1998). The differential expression of ER and ERß in cancer cells and experimental data on their respective roles on proliferation are reviewed in this report.

	Differential ERß expression as a common feature of estrogen-dependent tumor progression in clinical studies

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

 
Analysis of ER and ERß expression in estrogen-sensitive cancers (Tables 1–4)

In breast tissues, several studies have indicated an increase in ER/ERß mRNA and protein ratios in cancer as compared with benign tumors and normal tissues. In immunochemical analyses, Roger et al. (2001) found a higher percentage of ERß-positive cells in normal mammary glands than in nonproliferative benign breast disease (BBD) (85%), proliferative BBD without atypia (18.5%) and carcinoma in situ (33.8%). In contrast, an increase in ER protein expression was noted during progression. Moreover, ERß was inversely correlated with Ki67, a marker of cell proliferation. The authors thus suggest that ERß protects against the mitogenic activity of estrogens in mammary premalignant lesions. This conclusion is also supported by the results of another study (Shaw et al. 2002), which revealed lower ERß protein expression in carcinomas and demonstrated that ER, but not ERß, protein expression was correlated with tumor grade. Similar findings were obtained at the mRNA level by the RT-PCR method by Iwao et al. (2000), who also showed that ER mRNA is increased and ERß mRNA decreased during breast carcinogenesis. Recently, Park et al. (2003) compared ERß mRNA levels in various breast tissues, using mRNA in situ hybridization. ERß expression was decreased in BC and metastatic lymph node tissues as compared with normal mammary and benign breast tumor (BBT) tissues. The intensity and extent of ERß expression were significantly higher in normal and BBT tissues than in BC or metastatic lymph node tissues (Park et al. 2003).

In invasive BC, other studies using immunohisto-chemistry (IHC) and in situ hybridization revealed that ERß expression was associated with indicators of low biologic aggressiveness (low tumor grade, low S-fraction and negative lymph node status), suggesting that ERß might be a good prognostic indicator (Jarvinen et al. 2000). Omoto et al. (2001) in a survival analysis showed that patients with ERß-positive tumors had increased disease-free survival at 5 years as compared with those with ERß-negative tumors. Fuqua et al. (2003) studied ERß expression using IHC in a pilot series of 242 BC patients and showed that ERß expression is not associated with clinical and biologic parameters, including progesterone receptor (PR) expression, tumor grade and S-phase fraction. ERß was found to be correlated only with aneuploidy. The findings of this study suggested that ERß could be a useful biomarker on its own in clinical breast tumors. To gain insight into the possible role of ERß in breast carcinogenesis, Skliris et al. (2003) did an IHC analysis of ERß in 512 breast specimens. Moreover, real-time PCR was used to investigate the ERß gene methylation status in the ERß-negative BC cell lines SK-BR-3 and MDA-MB-435. The results suggested that the loss of ERß expression is one of the hallmarks of breast carcinogenesis, and that it may be a reversible process involving methylation. Zhao et al. (2003) also concluded that decreased ERß mRNA expression may be associated with breast tumorigenesis and that DNA methylation is an important mechanism for ERß gene silencing in BC (Table 1). Collectively, ERß expression decreases in the process of BC development.

View this table: [in this window] [in a new window]   Table 1 Relative expression of ER and ERß in breast tumor progression

View this table: [in this window] [in a new window]   Table 2 Relative expression of ER and ERß in ovarian tumor progression

View this table: [in this window] [in a new window]   Table 4 Relative expression of ER and ERß in colon tumor progression

Although many reports suggest the protective role of ERß against tumor progression, controversies have arisen regarding the clinical value of ERß expression in terms of predicting the adjuvant hormonal therapy response in breast cancer. Some studies suggest that the ERß status in BC is a predictor of the response to tamoxifen (Leygue et al. 1998, Jarvinen et al. 2000, Mann et al. 2001) whereas others suggest that ERß is significantly upregulated in tamoxifen-resistant breast cells and could be involved in tamoxifen resistance (Speirs et al. 1999).

The type of analysis, patient selection criteria, the type of splicing variants detected in RNA analyses or the small number of patients analyzed to date could ultimately explain these controversial results. The first findings were obtained in studies involving RT-PCR-based techniques, but the quantification of gene expression at the mRNA level may not be directly linked qualitatively or quantitatively to the protein expression. There have been very few studies in which ERs were measured by Western immunoblotting or IHC because of the lack of reliable antibodies. Finally, the choice of statistical analysis and different parameters selected for analysis could also influence the results.

ERß as a potential tumor-suppressor gene?

The results of these different studies, showing a loss of ERß expression in cancer as compared with normal cells, are in line with the hypothesis that the ERß gene may act as a tumor suppressor (Iwao et al. 2000). This concept needs to be confirmed but could make sense in view of the location of ERß on chromosome 14q (Enmark et al. 1997). A loss of 14q has been detected by comparative genomic hybridization in some breast cancers (Burki et al. 2000, Loveday et al. 2000). Interestingly, in ovarian cancer, two potential tumor-suppressor gene loci have been mapped to 14q (Bandera et al. 1997). 14q deletions are also observed in colon carcinoma (Young et al. 1993) and prostate cancer (Kasahara et al. 2002). These overall findings suggest a potential tumor-suppressive function for ERß. However, further studies are required before definitive conclusions on the tumor-suppressive function of ERß can be drawn.

	What are the potential molecular mechanisms underlying ER and ERß differential actions?

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

 
Several in vitro studies have focused on the molecular mechanisms underlying the differential roles of ER and ERß. Differences in ligand affinity, transcriptional activation, interactions with cofactors or putative heterodimerisation have been proposed.

Structural properties of ER and ERß and effects on their transcriptional activities

ER and ß belong to the large nuclear steroid/thyroid hormone receptor family. Like most other members of the family, ERs have a modular architecture of four interacting domains: the N-terminal A/B domain, the C or DNA-binding domain (DBD), the D or hinge domain and the C-terminal E/F or ligand-binding domain (LBD) (Fig. 1). There is only 56% amino-acid identity between the two receptors in the LBD, whereas the homology in the DBD is 97%. This suggests that ERß would recognize and bind to the same EREs as ER, but that each receptor might have a distinct spectrum of ligands (Kuiper & Gustafsson 1997). A number of novel selective ER subtype ligands have now been developed. The propyl pyrazole triol (PPT) compound was found to be an ER-specific agonist, activating gene transcription only through ER (Sun et al. 1999, Stauffer et al. 2000). A number of other known ligands are also somewhat ERß selective. Some phytoestrogens, such as genistein and coumestrol, show a higher affinity toward ERß than ER (Kuiper & Gustafsson 1997). The diarylpropionitrile (DPN) compound is a potency-selective agonist for ERß with a more than 70-fold higher binding affinity for ERß than ER (Meyers et al. 2001). Recently, Ghosh et al. (2003) have investigated a novel series of heterocycle ligands for the ERs based on a diazene core motif. In this process, they have found diazenes that have high binding affinity for the ERs, and some of these show preferential affinity for ER or for ERß.

View larger version (18K): [in this window] [in a new window]   Figure 1 Schematic representation of the structure of human (h)ER and ERß nuclear receptors. The A/B domain at the NH-2 terminal contains the ligand-independent transcriptional-activation function AF-1, the C domain represents the DNA-binding-domain, the D domain corresponds to the hinge region, and the E domain contains the hormone-binding domain and the hormone-dependent transcriptional-activation function AF-2. Numbers outside each box refer to amino acid number, whereas the number inside each box of ERß refers to the percentage of amino acid identity. The arrow indicates the translation starting site in ER cDNA.

ER and ERß are capable of regulating gene transcription through a classical mechanism involving the consensus ERE, but ERß seems to be a weaker transactivator (Cowley et al. 1999). Cowley and Parker (1999) have shown that the AF-1 activity of ERß is weak compared with that of ER on estrogen-responsive reporters, whereas their AF-2 activities are similar. In turn, when both AF-1 and AF-2 functions are active in a particular cell and/or on a particular promoter, the activity of ER greatly exceeds that of ERß, whereas ER and ERß activities are similar when only AF-2 is required (McInerney et al. 1998, Cowley et al. 1999). ER and ERß have similar but also different effects on gene transcription mediated via the ERE. To date, only a limited number of genes have been shown to be regulated by one of the two E2-liganded ER subtypes in this classical mode of action. In this way, the gene encoding the catalytic subunit of human telomerase hTERT is regulated by ER, and not by ERß in human ovary epithelium cells (Misiti et al. 2000) and in human prostate cancer (Nanni et al. 2002). In the same way, Lazennec et al. (2001) reported that, ER, but not ERß, was able to regulate c-myc proto-oncogene expression. The metallothionein gene is known to be specifically upregulated by E2 via ERß in SAOS-2 cells (Harris et al. 2001). However, recently, Stossi et al. (2004) have compared the generegulatory activities of ER and ERß in bone and showed high similarity but also significant differences in gene targets for these two ERs. Thus, genes encoding for cystatin D, autotaxin or stromal antigen 2 appear to be E2-regulated specifically by ERß in human osteosarcoma cells.

Estrogens (and antiestrogens) also transcriptionally regulate target genes via ERs though a non-ERE mode of action. These effects are mediated through promoter elements that bind various transcription factors, including AP-1-binding sites (Webb et al. 1995), Sp1 binding sites (Porter et al. 1997), SF1 response element (SFRE) (Vanacker et al. 1999), electrophophilic/antioxidant response element (EpRE/ARE) (Montano et al. 1997) and cyclic AMP response element (CRE) (Sabbah et al. 1999). At AP-1 sites, ER and ERß could have opposite transcriptional effects in some circumstances (Paech et al. 1997). In fact, ERß is able to potentiate an AP-1-containing reporter in the presence of the antiestrogen tamoxifen, but not in the presence of estrogens in a tissue-specific manner. ER stimulates AP-1 activity in the presence of antiestrogens in endometrial cells (Webb et al. 1995, Paech et al. 1997), but antiestrogens decrease or have no effect on AP-1 activity in BC cells (Philips et al. 1993, Webb et al. 1995). Of particular note, ERß is more potent overall than ER on AP-1 sites, whereas the contrary occurs on EREs (Paech et al. 1997, Cowley et al. 1999, Hall et al. 1999). Similar to AP-1, E2 binding to ER induces transcriptional activation when associated with SP1 in GC-rich regions. However, E2 interaction with ERß does not result in the formation of a transcriptionally active complex at a promoter containing Sp1 elements (Saville et al. 2000). Vanacker et al. (1999) found that the osteopontin gene promoter is stimulated through SFRE sequences by ER, but not by ERß.

Consequently, these differences in ligand interaction or transcriptional activity between the two ER subtypes may account for the major differences in their tissue-specific biologic actions. This complexity is further enhanced by ERß isoforms, the ability of ERs to form homodimers and heterodimers, and their capacity to interact with various coregulators.

ER isoforms

Several groups have reported and cloned different ERß isoforms with exon deletions (Lu et al. 1998), insertions (Hanstein et al. 1999), or C-terminal splice variants (Moore et al. 1998, Ogawa et al. 1998). These isoforms can also bind ligands, mediate estrogen signaling (Kuiper & Gustafsson 1997, Paech et al. 1997, Cowley et al. 1999, Bollig et al. 2000) and exhibit different properties, thus further enhancing the complexity in the spectrum of potential cellular responses to estrogen. The key element lies perhaps in the balance between the expression of these different variants and their relative quantities. It has been shown that ERß splice variants have dramatically different localization patterns in living cells, and this localization can be altered by estrogen agonists and antagonists (Price et al. 2001). Interestingly, Poola et al. (2002) recently showed that ERß splice variant mRNAs were differentially altered during breast carcinogenensis. ERß cx, which utilizes an alternative exon 8, is the most extensively studied splice variant. Ogawa et al. (1998) showed that this isoform may act as a potential inhibitor of ER transactivation, possibly due to ER/ERßcx heterodimer formation. Using IHC, it has been shown that differential expression of ERßwt and ERßcx may be used as a prognostic marker in human prostate (Fujimura et al. 2001). Peng et al. (2003) showed that all ERß isoforms inhibited ER transcriptional activity on an ERE, while only ERßwt had transcriptional activity of its own. It has been shown, using cDNA microarrays in MCF-7 cells stably transfected with ERßwt and ERßcx MCF-7, that these two isoforms inhibit ER function differently (Omoto et al. 2003). Consequently, it can be hypothesized that the differential expression of ERß isoforms may have a role in the modulation of estrogen action.

ER homo- and heterodimers

The functional formation of ER and ERß heterodimers has been demonstrated (Cowley et al. 1997, Pettersson et al. 1997). They are able to bind to DNA with an affinity similar to that of ER and greater than that of ERß homodimers, to interact with coactivators, and to stimulate the transcription of reporter gene in transfected cells (Cowley et al. 1997, Pettersson et al. 1997). The possible involvement of ER and ERß dimerization would increase the complexity of transcription activation in response to E2, suggesting the existence of two previously unrecognized estrogen-signaling pathways, that is, ERß homodimers and ER/ERß heterodimers. Moreover, it has been reported that various ER and ERß ratios in different cells, resulting in different homodimer and heterodimer compositions, may constitute a key to gaining insight into the tissue-specific effects of estrogen and antiestrogens (Kuiper et al. 1997). Homodimers and heterodimers could bind to distinct response elements and consequently activate specific gene-expression patterns in given target tissues. For such interactions, ER and ERß must be coexpressed in cells, as noted in breast, ovarian and endometrium tissues. However, future studies will be required to determine the physiologic roles of ER and ERß homo- and heterodimers in vivo.

Interactions with coactivators and corepressors

There is one further confounding factor in the ER-mediated estrogen action equation. The ER-mediated transcriptional activity of estrogen is influenced by several regulatory factors, known as coactivators and corepressors, which activate or repress the transcription of ER-responsive genes (Klinge et al. 2000). The p160/SRC (steroid receptor coactivator) family is one of the most studied classes of coactivators, and it includes SRC1, SRC2 (GRIP1/TIF-2) (McKenna et al. 1999) and other more recently described coactivators such as ACTR (Chen et al. 1997), RAC3 (Li et al. 1997), AIB1 (Anzick et al. 1997) and TRAM-1 (Takeshita et al. 1997). Most of interactions of these coregulators with the ER are ligand-dependent, but some coactivators have also been shown to be recruited in a ligand-independent manner by the AF-1 domain of ERs (McInerney et al. 1996, Tremblay et al. 1999). SRC-1 activated ERßAF-1 upon MAPK-induced phosphorylation of serine residues (Tremblay et al. 1999). Deblois et al. (2003) studied the steroid receptor RNA activator (SRA) and showed that SRA potentiated the estrogen-induced transcriptional activity of both ER and ERß. They demonstrated that the transcriptional activity of ER can be enhanced by SRA in a ligand- independent manner through the AF-1 domain. However, this AF-1-dependent effect of SRA is not observed on ERß. Very few receptor-specific ERß cofactors have been identified so far. Warnmark et al. (2001) showed that TRAP220 displays a preference for ERß and suggested that the coregulator selectivity of ER subtypes is an additional layer of specificity that influences the transcriptional response in estrogen target cells. Using multiplex RT-PCR, Kurebayashi et al. (2000) also showed that ERß-expression levels were correlated with some activators such as AIB1, CBP, P/CAF, and a corepressor, N-CoR, but the significance of this correlation is unclear. Nuclear receptors usually bind the corepressors N-CoR and SMRT in the absence of ligand or in the presence of antagonists. Agonist binding leads to corepressor release and coactivator recruitment. Webb et al. (2003) recently demonstrated that, in vitro and in vivo, ERß binds to N-CoR and SMRT in the presence of ER agonists, such as estradiol, and phytoestrogens, such as genistein, but not in the presence of antagonists. ER and ERß present completely distinct modes of action with coregulators, a fact which could be of major importance in terms of potential effects on physiologic behavior (Webb et al. 2003).

	What do we know about the role of ERß in cell proliferation and death?

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

 
ERß and cell proliferation

Although the specific functions of ERß in cancer are not known, there is some evidence that ERß could have inhibitory effects on cellular proliferation. First, as indicated previously, the levels of ERß are highest in normal tissue (breast, ovary and prostate) as well as in benign disease, and they decrease during carcinogenesis (Tables 1–3). Our laboratory obtained the first evidence that ERß is an important modulator of proliferation and invasion of breast and ovarian cancer cells, thus supporting the hypothesis that the loss of ERß expression could be one of the events leading to breast and ovarian cancer development (Lazennec et al. 2001, Bardin et al. 2004). Whereas ER was able to regulate reporter genes and endogenous genes in a ligand-dependent manner, ERß inhibited MDA-MB231 cell proliferation in a ligand-independent manner. This suggests that the two ERs inhibit cancer cell proliferation via different mechanisms (Lazennec et al. 2001).

Omoto et al. (2003) recently developed cell lines expressing ERß wt and ERß cx by stable transfection of each expression plasmid in MCF7 cells and demonstrated that this constitutive expression significantly reduced the percentage of cell population in S-phase and the number of colonies in an anchorage-independent assay. Recently, two studies showed that the induced expression of ERß in ER-positive BC cells inhibits their growth (Paruthiyil et al. 2004, Strom et al. 2004). These reports also suggest that ERß might reduce cell proliferation by inhibiting the cyclin D1 gene, a key factor controlling the G1-S transition of the cell cycle, and thus cell proliferation. Strom et al. (2004) also indicated that numerous other components of the cell cycle associated with proliferation, such as cyclin E or Cdc25A, were decreased. These results are in accordance with the study of Bièche et al. (2001), showing a negative correlation between ERß and CCND1 (cyclin D1) expression. In vitro studies support the hypothesis of Liu et al. (2002), who showed that E2 activates cyclin D1 gene transcription through ER, but inhibits cyclin D1 gene transcription through ERß in HeLa cells.

The contrasting phenotypes observed in individual lines of ER^–/– mice, that is, ER KO and ERßKO, which exhibit phenotypes that generally mirror the respective ER-expression patterns, provides further evidence that the two ERs have distinct biologic functions. Weihua et al. (2000) observed that, in the immature uterus, ER and ERß are expressed at comparable levels in the epithelium and stroma, and E2 treatment decreases ERß in the stroma. Increased cell proliferation and the exaggerated response to E2 in ERßKO mice suggests that ERß plays a role in the modulation of the effects of ER and also (or consequently) has an antiproliferative function in the immature uterus. A second study in ERß^–/– mice showed that ERß is implicated in the regulation of epithelial growth, and its absence results in hyperplasia of the prostatic epithelium (Weihua et al. 2001). The inhibition of ER transcriptional activity could be a molecular mechanism by which ERß has antiproliferative effects. Previous in vitro data indicate that ERß could act as a dominant negative regulator of ER activity. Hall et al. (1999) have provided direct proof that ERß modulates or represses ER transcriptional activity in transient transfection cells. In bone, it has been shown that ERß inactivation by gene targeting results in increased cortical bone formation. Windalh et al. (2001) showed that, when present, ERß acts in a repressive manner on trabecular bone, possibly by inhibiting the stimulatory action of ER . Finally, Lindberg et al. (2003) showed that in some mouse tissues, ERß reduces ER-regulated gene transcription, thus indicating that there is a balanced relationship between ER and ERß (Fig. 2).

View larger version (20K): [in this window] [in a new window]   Figure 2 Schematic representation of ER and ERß imbalance in estrogen-dependent tumor progression.

	ERß and apoptotic pathways?

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

View larger version (32K): [in this window] [in a new window]   Figure 3 Hypothetical mode of ERß action on cell proliferation pathways.

	Conclusions

Top Abstract Introduction Differential ERß... What are the potential... What do we know... ERß and apoptotic... Conclusions References

ER and ERß have some overlapping tissue distribution but also display high relative tissue-specific expression. Moreover, a number of molecular mechanisms may explain the differential roles of ER and ERß, including differences in ligand affinity and transactivation, distinct cofactor interactions and putative heterodimerization. Splicing variant ERs isoforms may also be important in modulating the cellular response.

In conclusion, the imbalance in ER/ERß expression in estrogen-dependent cancer opens a new field in hormone therapy of cancer. Targeted ERß therapies, including the development of ERß specific ligands, may constitute a new therapeutic approach, particularly for pre-invasive or proliferative lesions. The clinical value of ERß in cancer prognosis and its possible usefulness for prediction of the hormone response should be assessed in large-scale and prospective clinical studies.

	Acknowledgements

 
This work was supported by the Ligue Nationale Contre le Cancer, the Centre Hospitalier Universitaire de Montpellier (grant no. AOI7619), the Association pour la Recherche contre le Cancer (grant no. 4302) and the Institut National de la Santé et de la Recherche Médicale.

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