CXCR4 and CXCR7 are the two receptors for the chemokine CXCL12, a key mediator of the growth effect of estrogens (E2) in estrogen receptor (ER)-positive breast cancers. In this study we examined E2-regulation of the CXCL12 axis components and their involvement in the growth of breast cancer cells. CXCR4 and CXCR7 were differentially regulated by E2 which enhanced the expression of both CXCL12 and CXCR4 but repressed the expression of CXCR7. Formaldehyde-associated isolation of regulatory elements (FAIRE) revealed that E2-mediated transcriptional regulation of these genes is linked to the control of the compaction state of chromatin at their promoters. This effect could be accomplished via several distal ER-binding sites in the regions surrounding these genes, all of which are located 20–250 kb from the transcription start site. Furthermore, individual down-regulation of CXCL12, CXCR4 or CXCR7 expression as well as the inhibition of their activity significantly decreases the rate of basal cell growth. In contrast, E2-induced cell growth was differentially affected. Unlike CXCR7, the inhibition of the expression or activity of either CXCL12 or CXCR4 significantly blunted the E2-mediated stimulation of cellular growth. Besides, CXCR7 over-expression increased the basal MCF-7 cell growth rate and decreased the growth effect of E2. These findings indicate that E2 regulation of the CXCL12 signaling axis is important for the E2-mediated growth effect of breast cancer cells. These data also provide support for distinct biological functions of CXCR4 and CXCR7 and suggest that targeting CXCR4 and/or CXCR7 would have distinct molecular effects on ER-positive breast tumors.

The results from recent studies show that some benzophenones (BPs) and their hydroxylated metabolites can function as weak estrogens (E2) in the environment. However, little is known about the structure-activity relationship of these molecules. We have examined the effects of exposure to ten different BPs on the proliferation of estrogen receptor (ER)-positive breast cancer cells and on the transcriptional activity of E2-target genes. We analyzed two genes that are tightly linked with estrogen-mediated proliferation, the CXCL12 and amphiregulin genes and two classical estrogen-responsive genes, the pS2 and progesterone receptor. Significant differences in the BPs efficiency to induce cell proliferation and endogenous E2-target gene expressions were observed. Using ERE-, Sp1-, AP1- and C3-reporter genes that contain different ER-binding sites in their promoter, we also showed significant differences in the BPs efficiency in activation of the ER transactivation. Together, our analyzes showed that the most active molecule is 4-hydroxy-BP. Docking analysis of the interaction of BPs in the ligand-binding pocket of ERα suggests that the minimum structural requirement for the estrogenic activity of BPs is a hydroxyl (OH) group in the phenyl A-ring that allows interaction with Glu-353, Arg-394 or Phe-404, which enhances the stability between BPs and ERα. Our modeling also indicates a loss of interaction between the OH groups of the phenyl B-ring and His-524. In addition, the presence of some OH groups in the phenyl B-ring can create repulsion forces, which may constrain helix 12 in an unfavorable position, explaining the differential estrogenic effects of BPs. These results, together with our analysis of BPs for their potency in activation of cell proliferation and ER-mediated transcription, report an improved understanding of the mechanism and structure–activity relationship of BPs.

The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERβ) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens.

In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel ofin vivoandin vitrobioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens.

Radiofrequency radiations constitute a new form of environmental pollution. Among them, millimeter waves (MMW) will be widely used in the near future for high speed communication systems. This study aimed therefore to evaluate the biocompatibility of MMW at 60 GHz. For this purpose, we used a whole gene expression approach to assess the effect of acute 60 GHz exposure on primary cultures of human keratinocytes. Controls were performed to dissociate the electromagnetic from the thermal effect of MMW. Microarray data were validated by RT-PCR, in order to ensure the reproducibility of the results. MMW exposure at 20 mW/cm², corresponding to the maximum incident power density authorized for public use (local exposure averaged over 1 cm²), led to an increase of temperature and to a strong modification of keratinocyte gene expression (665 genes differentially expressed). Nevertheless, when temperature is artificially maintained constant, no modification in gene expression was observed after MMW exposure. However, a heat shock control did not mimic exactly the MMW effect, suggesting a slight but specific electromagnetic effect under hyperthermia conditions (34 genes differentially expressed). By RT-PCR, we analyzed the time course of the transcriptomic response and 7 genes have been validated as differentially expressed: ADAMTS6, NOG, IL7R, FADD, JUNB, SNAI2 and HIST1H1A. Our data evidenced a specific electromagnetic effect of MMW, which is associated to the cellular response to hyperthermia. This study raises the question of co-exposures associating radiofrequencies and other environmental sources of cellular stress.