Case Report: Atypical acute compartment syndrome of the forearm in a child following minor trauma with consecutive osteomyelitis.

Introduction: Forearm compartment syndrome (CS) in children is above all a clinical diagnosis whose main cause is traumatic. However, rarer causes such as infection can alter its clinical presentation. Clinical case: An 8-year-old boy has been seen in the emergency department complaining of severe forearm pain under a splint in a mild traumatic context. The previous radiological imaging examination three days before had not revealed any fractures. On admission, he presented with major signs of skin inflammation, loss of mobility, paresthesia and a significant biological inflammatory syndrome. The acute CS diagnosis has been made and was treated, but its atypical presentation raised a series of etiological hypotheses, in particular infectious, even if it remains rare. Complementary imaging examinations confirmed the presence of osteomyelitis of the distal radius as well as an occult Salter-Harris II fracture. Discussion: Beyond the classic "five P's of CS" -pain, paresthesia, paralysis, pallor and pulselessness-, CS's clinical presentations are multiple, especially in pediatric patients. In children, severe pain and increasing analgesic requirement must be indicators of a CS. We hypothesize that this patient sustained a nondisplaced Salter-Harris II fracture with a hematoma colonized by hematogenous osteomyelitis explaining its initial clinical presentation. Conclusion: Hematogenous osteomyelitis complicated by CS is rare and may be accompanied by a traumatic history. It's atypical presentation in pediatric patients requires vigilance and prompt diagnosis given the disastrous and irreversible complications.

[74-year-old man with a complex acromio-clavicular disjunction]. / Luxation acromio-claviculaire complexe chez un patient de 74 ans.

Acromioclavicular dislocation is a frequent pathology commonly encountered in traumatology. Therefore, its management is generally standardized, guided by clinical and radiological evaluation. This can range from conservative treatment by limb immobilization and functional rehabilitation, to surgical treatment by using minimally invasive techniques. We present the particular case of a 74-year-old patient with an acromioclavicular dislocation associated with a non-displaced fracture of the coracoid process as well as of the spine of the scapula. This article aims to describe the diagnostic traps as well as discuss the treatment options for this complex presentation.

La luxation acromio-claviculaire est une pathologie fréquemment rencontrée lors de la pratique courante en traumatologie. Par conséquent, sa prise en charge est généralement standardisée, guidée par l'évaluation clinique et radiologique. Celle-ci peut aller du traitement conservateur par immobilisation du membre et rééducation fonctionnelle, au traitement chirurgical pouvant se faire désormais selon des techniques mini-invasives. Nous présentons le cas particulier d'un patient de 74 ans présentant une luxation acromio-claviculaire associée à une fracture non-déplacée du processus coracoïde ainsi que de l'épine de la scapula. Cet article a pour but de décrire les pièges diagnostiques, ainsi que de discuter des options thérapeutiques concernant cette présentation complexe.

[Interest of non invasive navigation in total knee arthroplasty]. / Intérêt de la navigation non invasive dans l'arthroplastie totale de genou.

During surgery of total knee arthroplasty, we use a computerized non invasive navigation (Brainlab Victor Vision CT-free) to assess the accuracy of the bone cuts (navigation expresse). The purpose of this study is to evaluate non invasive navigation when a total knee arthroplasty is achieved by conventional instrumentation. The study is based on forty total knee arthroplasties. The accuracy of the tibial and distal femoral bone cuts, checked by non invasive navigation, is evaluated prospectively. In our clinical series, we have obtained, with the conventional instrumentation, a correction of the mechanical axis only in 90 % of cases (N = 36). With non invasive navigation, we improved the positioning of implants and obtained in all cases the desired axiometry in the frontal plane. Although operative time is increased by about 15 minutes, the non invasive navigation does not induce intraoperative or immediate postoperative complications. Despite the cost of this technology, we believe that the reliability of the procedure is enhanced by a simple and reproducible technique.

Vascular chronic Q fever: quality of life.

The aim of this study was to evaluate the quality of life in patients with vascular chronic Q fever at time of diagnosis and during follow-up. Based upon the SF-36 questionnaire, the mean physical and mental health of each patient were assessed at 3-month intervals for up to 18 months. A total of 26 patients were included in the study. At time of diagnosis, the mean physical health and mental health score was 50·6 [95% confidence interval (CI) 46·7-54·4] and 44·6 (95% CI 41·6-47·5), respectively. During treatment, the mean physical health score declined significantly by 1·7 points each 3 months (P < 0·001) to 40·8 (95% CI 34·4-45·1). The mean mental health score significantly and steadily increased towards 51·2 (95% CI 46·9-54·3) during follow-up (P = 0·026). A total of 23% of patients were cured after 18 months of follow-up. In conclusion, quality of life at time of diagnosis for patients with vascular chronic Q fever is lower compared to a similar group of patients, matched for age and gender, with an aortic abdominal aneurysmal disease, and physical health decreases further after starting treatment. Considering the low percentage of cure, the current treatment of vascular chronic Q fever patients may require a separate strategy from that of endocarditis in order to increase survival.

In vitro generation of mature, naive antigen-specific CD8(+) T cells with a single T-cell receptor by agonist selection.

Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8(+) T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4(+)CD8(+) double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8(+) T cells. Comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8(+) T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimer-reactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing.

Identification of polyproline II regions derived from the proline-rich nuclear receptor coactivators PNRC and PNRC2: new insights for ERα coactivator interactions.

Protein-protein interactions are crucial for signal transductions required for cell differentiation and proliferation. Their modulation is therefore key to the development of therapeutic alternatives, particularly in the context of cancer. According to literature data, the polyproline-rich nuclear receptor coactivators PNRC and PNRC2 interact with estrogen receptor (ERα) through their PxxP SH3-binding motifs. In a search to identify the molecular features governing this interaction, we explored using electronic circular dichroism (ECD) spectroscopy and molecular dynamics (MD) calculations, the capacity of a range of putative biologically active peptides derived from these proteins and containing this PxxP motif(s) to form polyproline II (PPII) domains. An additional more exhaustive structural study on a lead PPII peptide was also performed using 2D nuclear magnetic resonance (NMR) spectroscopy. With the exception of one of all the investigated peptides (PNRC-D), binding assays failed to detect any affinity for Grb2 SH3 domains, suggesting that PPII motifs issued from Grb2 antagonists have a binding mode distinct from those derived from Grb2 agonists. Instead, the peptides revealed a competitive binding ability against a synthetic peptide (ERα17p) with a putative PPII-cognate domain located within a coregulator recruitment region of ERα (AF-2 site). Our work, which constitutes the first structure-related interaction study concerning PNRC and PNRC2, supports not only the existence of PxxP-induced PPII sequences in these coregulators, but also confirms the presence of a PPII recognition site in the AF-2 of the steroid receptor ERα, a region important for transcription regulation.

Notch induces human T-cell receptor γδ+ thymocytes to differentiate along a parallel, highly proliferative and bipotent CD4 CD8 double-positive pathway.

In wild-type mice, T-cell receptor (TCR) γδ(+) cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCRαß(+) cells differentiate along the double-positive (DP) pathway. In the human postnatal thymus (PNT), DN, DP and single-positive (SP) TCRγδ(+) populations are present. Here, the precursor-progeny relationship of the various PNT TCRγδ(+) populations was studied and the role of the DP TCRγδ(+) population during T-cell differentiation was elucidated. We demonstrate that human TCRγδ(+) cells differentiate along two pathways downstream from an immature CD1(+) DN TCRγδ(+) precursor: a Notch-independent DN pathway generating mature DN and CD8αα SP TCRγδ(+) cells, and a Notch-dependent, highly proliferative DP pathway generating immature CD4 SP and subsequently DP TCRγδ(+) populations. DP TCRγδ(+) cells are actively rearranging the TCRα locus, and differentiate to TCR(-) DP cells, to CD8αß SP TCRγδ(+) cells and to TCRαß(+) cells. Finally, we show that the γδ subset of T-cell acute lymphoblastic leukemias (T-ALL) consists mainly of CD4 SP or DP phenotypes carrying significantly more activating Notch mutations than DN T-ALL. The latter suggests that activating Notch mutations in TCRγδ(+) thymocytes induce proliferation and differentiation along the DP pathway in vivo.

La salud en el trabajo: nueva visión y profesiones de futuro Propuestas para la formación y para una red de investigación acordes con sus misiones / No disponible

La medicina del trabajo está en peligro. De aquí a 5 años, si no se toman medidas para ayudar a los profesionales de la salud en el trabajo a anticipar las jubilaciones de los “praticiens”1 y de los docentes hospitalo-universitarios, este dispositivo único en el mundo, que concierne en Francia a cerca de 16 millones de asalariados, podría extinguirse, falto de falto “expertise” y de perspectivas (AU)

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Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have defective CD4(+)CD25(+) regulatory T (T(reg)) cells and increased osteoclastogenesis. A similar situation has been described in collagen-induced arthritis (CIA). In this study, it was investigated whether a single transfer of polyclonally activated T(reg) cells inhibits CIA and osteoclastogenesis. METHODS: Purified T(reg) cells were expanded in vitro with anti-CD3 and anti-CD28 antibody-coated beads and injected into DBA/1 mice. Mice were immunised with collagen type II (CII) in complete Freund adjuvant (CFA) and scores of arthritis were recorded. In vitro osteoclastogenesis assays were performed on splenocytes by stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)kappaB ligand (RANKL). Levels of anti-CII antibody and cytokines were determined in the supernatant using ELISA and Bio-Plex protein array system. RESULTS: It was found that 10(6) activated T(reg) cells significantly counteracted the development of CIA, which was accompanied by decreased serum levels of TNFalpha and IL6, but not by inhibition of autoimmune antibody responses. The differentiation of osteoclasts in splenocyte cultures was significantly reduced in the presence of prestimulated T(reg) cells. Expression of cytokines that are described to inhibit osteoclastogenesis, including granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)gamma, interleukin (IL)5 and IL10, were dramatically increased upon addition of T(reg) cells. Furthermore, splenocytes from mice that had been treated with T(reg) cells displayed an impaired capacity to develop into mature osteoclasts, suggesting that T(reg) cells abrogated osteoclastogenesis in vivo. CONCLUSIONS: Activated CD4(+)CD25(+) T(reg) cells improve clinical symptoms of CIA, regulate cytokine production and inhibit osteoclastogenesis in vitro and in vivo.

Human intrathymic development: a selective approach.

Human T lymphocytes can be generated from CD34 progenitor cells from different sources. This can be obtained in an in vivo model wherein human thymic tissue and fetal liver is transplanted in an immunodeficient mouse. However, human T cells are also generated in immunodeficient mice without co-transplantation of human thymus or in in vitro hybrid human-mouse fetal thymus organ culture. This shows that xenogeneic mouse thymus tissue supports human T cell differentiation. Finally, human T cells are generated on co-culture with murine stromal cells that express the Delta-like1 ligand for the Notch receptor. How these different environments influence the human T cell repertoire is reviewed and discussed.

Comparative clinical and transcriptomal profiles of breast cancer between French and South Mediterranean patients show minor but significative biological differences.

BACKGROUND: In Western countries, breast cancer incidence and mortality are higher than in Mediterranean countries. These differences have been ascribed to environmental factors but also to late-stage diagnostic and biological specific characteristics. PATIENTS AND METHODS: Between September 2002 and September 2005, we collected clinical data by phone counselling 180 French and Mediterranean breast cancer patients and performed microarray experiments. RESULTS: Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive (more SBR grade III and positive node invasion) and patients were 10 years younger at diagnosis. Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. Additionally, an up-regulation of cytokeratins KRT8 and KRT18 may indicate a luminal B subtype in "South" (Lebanon, Tunisia and Morocco) tumors while "North" (France) tumors may more frequently be luminal A type. CONCLUSION: This study allowed the identification of specific clinical and transcriptomic parameters in patients from South Mediterranean countries.

T-, B- and NK-lymphoid, but not myeloid cells arise from human CD34(+)CD38(-)CD7(+) common lymphoid progenitors expressing lymphoid-specific genes.

Hematopoietic stem cells in the bone marrow (BM) give rise to all blood cells. According to the classic model of hematopoiesis, the differentiation paths leading to the myeloid and lymphoid lineages segregate early. A candidate 'common lymphoid progenitor' (CLP) has been isolated from CD34(+)CD38(-) human cord blood cells based on CD7 expression. Here, we confirm the B- and NK-differentiation potential of CD34(+)CD38(-)CD7(+) cells and show in addition that this population has strong capacity to differentiate into T cells. As CD34(+)CD38(-)CD7(+) cells are virtually devoid of myeloid differentiation potential, these cells represent true CLPs. To unravel the molecular mechanisms underlying lymphoid commitment, we performed genome-wide gene expression profiling on sorted CD34(+)CD38(-)CD7(+) and CD34(+)CD38(-)CD7(-) cells. Interestingly, lymphoid-affiliated genes were mainly upregulated in the CD7(+) population, while myeloid-specific genes were downregulated. This supports the hypothesis that lineage commitment is accompanied by the shutdown of inappropriate gene expression and the upregulation of lineage-specific genes. In addition, we identified several highly expressed genes that have not been described in hematopoiesis before.

Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells.

PURPOSE: Estrogen receptor alpha (ERalpha) plays a major role in breast cancer development. It acts as ligand-inducible transcription factor which determines growth, survival and differentiation of breast cancer cells. The aim of this study is to evaluate the potential interference between radiotherapy and estrogen receptor responsiveness. Materials and methods. The effect of ionizing radiation was assessed on the estrogen receptor alpha status, growth (proliferation and apoptosis) and sensitivity of MCF-7 breast cancer cells to estrogenic (17beta-estradiol (E2)), selective estrogen receptor modulator (SERM) and anti-estrogenic compounds. Results. We have observed a ligand-independent decrease in ERalpha expression after radiation, resulting from a specific reduction in mRNA level and protein synthesis. This ERalpha disappearance occurred 72 h post-irradiation at 8 Gy and decreased the transcriptional activity in ERalpha of these cells. On the other hand, E2 impedes the growth inhibitory effects (essentially on proliferation) of ionizing radiation in MCF-7 cells, which potentially decreases radiosensitivity of these cells. This effect was totally blocked by SERM and anti-estrogenic treatments. Moreover, this growth effect of concurrent anti-estrogenic drugs and ionizing radiation appeared to be strongly synergistic. CONCLUSIONS: This study may increase general comprehension of ERalpha modulation by radiotherapy and improve adjuvant therapeutic approaches based on co-administration of radiation and endocrine therapy.

[Emphysematous pyelonephritis with favourable outcome after conservative treatment]. / Une pyélonéphrite emphysémateuse d'évolution favorable après traitement conservateur.

Emphysematous pyelonephritis is a necrotizing renal infection characterized by bacterial gas production in the renal and perirenal area. It is a rare infection diagnosed in diabetic patients in most cases. Emphysematous pyelonephritis is responsible for a high mortality rate. We report the case of a woman, unknown diabetic, who presented with emphysematous pyelonephritis. Early diagnosis performed by CT-scan allowed effective and conservative surgical treatment and final positive outcome.

Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.

Tamoxifen is the standard first-line endocrine therapy for breast cancer, but recent data indicate that it is likely to be replaced by the effective aromatase inhibitors (AIs), in both the metastatic and adjuvant settings. Aromatase inhibitors induce complete oestrogen deprivation that leads to clinically significant bone loss. Several ongoing or planned trials combine AIs with bisphosphonates, even more so that recent data reveal that clodronate may reduce the incidence of bone metastases and prolong survival in the adjuvant setting. Bisphosphonates can inhibit breast cancer cell growth in vitro, but they have never been studied in steroid-free medium (SFM), an in vitro environment that mimics the effects of AIs in vivo. Quite surprisingly, in SFM, clodronate stimulated MCF-7 cell growth in a time- and dose-dependent manner by up to two-fold (crystal violet staining assay), whereas it had no mitogenic activity in complete medium. The bisphosphonate similarly increased the proliferation of IBEP-2 cells, which also express a functional oestrogen receptor (ER), while it weakly inhibited the growth of the ER-negative MDA-MB-231 cells. Expectedly, 17beta-oestradiol stimulated the growth of MCF-7 and IBEP-2 cells cultured in SFM, and had no effect on MDA-MB-231 cells. Moreover, partial (4-OH-tamoxifen) and pure antioestrogens (fulvestrant, ICI 182,780), in combination with clodronate, completely suppressed the mitogenic effect of the bisphosphonate, suggesting that it was mediated by an activation of ER. In accordance with this view, clodronate induced ER downregulation, weakly increased progesterone receptor expression, and stimulated the transcription of an oestrogen-responsive reporter gene. In conclusion, we report a previously unknown stimulatory effect of clodronate on MCF-7 cells grown in SFM, in vitro conditions that are potentially relevant to the use of AIs for breast cancer. Moreover, our data suggest that ER is involved in these effects of clodronate on cancer cell growth.

Stable 'portrait' of breast tumors during progression: data from biology, pathology and genetics.

It is widely believed that ductal breast cancer dissemination involves a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Such changes have frequently been attributed to the sequential acquisition of various alterations in a single cell followed by clonal selection and expansion, thus leading to intra-tumor diversity. According to this multi-step view, extensive genotype and phenotype (marker expression, grade) shift may occur in the same tumor during progression; this may lead to the co-existence of molecularly and/or pathologically different areas within the same lesion. An increasing amount of data of various natures now appear to challenge this concept: only a few distinct 'portraits', in relation to estrogen receptor (ER) status and grade, may be found among tumors. Moreover, although undergoing increasing genetic alteration, most individual lesions largely maintain their phenotype when they evolve from in situ to the metastatic state. While many of the data presented here are related to ductal tumors, lobular cancer is also discussed.

Gene regulation by phorbol 12-myristate 13-acetate in MCF-7 and MDA-MB-231, two breast cancer cell lines exhibiting highly different phenotypes.

We have examined the effects of the protein kinase C (PKC)-activator phorbol 12-myristate 13-acetate (PMA) on gene expression in two breast cancer cell (BCC) lines exhibiting highly different phenotypes. These are the estrogen receptor alpha (ERalpha)-positive, weakly invasive, luminal epithelial-like MCF-7 and the ERalpha-negative, highly invasive, fibroblast-like MDA-MB-231. They express constitutively low and high PKC activities, respectively. After a 24-h exposition to 100 nM PMA, the number of genes showing an altered expression at the 2-fold change level was much higher in MCF-7 (n=435) than in MDA-MB-231 (n=18) BCC. Four of these genes, namely CDC2, CENPA, NR4A1 and MMP10, were altered in the same way in both cell lines. Two genes were regulated in an opposite way: ID1 and EVA1. Many of the genes down-regulated in MCF-7 BCC appeared to be preferentially expressed in the G1, S, and/or G2 phases of the cell cycle. The ERalpha gene, ESR1, and other genes associated to the ERalpha-positive, luminal epithelial-like BCC phenotype were down-regulated, while a series of genes related to a more aggressive, fibroblast-like BCC phenotype were up-regulated. Other altered genes were notably linked to cell architecture, supporting profound effects of PMA on cell morphology and motility, as well as on the interactions between BCC and their neighboring proteins. Of note, all the modulated genes involved in proteolysis and its control were up-regulated. In summary, PMA effects suggest that PKC activation may induce, to some extent, a more fibroblast-like phenotype in the ERalpha-positive, luminal epithelial-like MCF-7 BCC, and significantly modulate the interactions of these cells with their environment.

The first organometallic selective estrogen receptor modulators (SERMs) and their relevance to breast cancer.

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.

Extracellular calcium downregulates estrogen receptor alpha and increases its transcriptional activity through calcium-sensing receptor in breast cancer cells.

Skeleton is the most common organ targeted by breast cancer cells, especially from estrogen receptor alpha (ER)-positive neoplasms. Metastatic cells can stimulate directly or indirectly osteoclast-mediated bone resorption. Tumor-induced osteolysis is often extensive and leads to the release of large quantities of calcium. Metastatic cancer cells can be thus exposed to high calcium concentrations (40 mM has been reported at the resorption site). However, the effects of Ca2+ on breast cancer cells have been minimally examined. We showed that 20-mM extracellular Ca2+ induced a downregulation of ER protein in MCF-7 cells and caused ER-mediated transactivation of a reporter gene by 55 +/- 10% (mean +/- SD) in MVLN cells (MCF-7 cells stably transfected with ERE and luciferase reporter gene). Moreover, 3 mM Ca2+ increased progesterone receptor (PgR) expression by 45 +/- 8%. Mg2+ tested at up to 20 mM did not exert any effects, while 17beta-estradiol downregulated ER, transactivated the reporter gene, and enhanced PgR expression. The pure antiestrogen ICI 182,780 was able to abrogate the transactivation of the reporter gene and the increase in PgR levels induced by Ca2+, indicating that Ca2+ may exert a weak and specific estrogenic effect in MCF-7 cells. Ca2+ effects on ER probably start at the cell membrane level since a large Ca2+ influx caused by the ionophore A23187 failed to activate ER. We have thus studied the involvement of the membrane calcium-sensing receptor (CaR) that is known to be expressed notably in MCF-7 cells. We first tested the effects of a specific activator of CaR. Exposure to 10(-4) M calcimimetic NPS R-467 mirrored the changes observed with extracellular Ca2+ by inducing a marked decrease in ER protein levels, increasing the transcriptional activity of ER (67 +/- 12%) and stimulating PgR expression (41 +/- 4%). As expected, the NPS S-467 isomer was less effective. Furthermore, a highly selective CaR antagonist partly suppressed the downregulation of ER as well as transactivation of the reporter gene induced by Ca(2+). Our results suggest that the effects of extracellular Ca2+ on ER expression and activity are mediated, at least in part, by the CaR. In summary, calcium released during the process of metastatic bone destruction could modulate the functions of the estrogen receptor, a key receptor involved in breast cancer cells growth and function, and thus participate in the pathogenesis of tumor-induced osteolysis.