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Mercatali L.,Osteoncology Center | Ibrahim T.,Osteoncology Center | Sacanna E.,Osteoncology Center | Flamini E.,Osteoncology Center | And 9 more authors.
International Journal of Oncology | Year: 2011

Osteoprotegerin (OPG) is a decoy receptor of the receptor activator of nuclear factor-κB ligand (RANK-L) and plays an important role in the formation of metastatic bone lesions. We evaluated the usefulness of circulating OPG and RANK-L for the detection of bone metastases. We enrolled 143 individuals in the study: 30 healthy donors (HD) and 113 breast cancer patients. Among patients, 49 had no evidence of disease (NEDP), 54 had bone metastases (BMP) at first diagnosis, and 10 had visceral metastases (VMP). Both transcripts were determined in peripheral blood samples using quantitative PCR. Receiver operating characteristic (ROC) curve analysis was used to calculate the diagnostic accuracy of OPG, RANK-L, CEA and CA15-3. OPG and RANK-L median values were significantly lower in BMP (median 0.5, range 0.1-5.7, p<0.001 and median 0.5, range 0.1-4.5, p=0.024, respectively) compared to NEDP (median 1.7, range 0.4-8.9 and median 0.8, range 0.2-3.8, respectively), regardless of the number and type of bone lesions or the presence of visceral metastases. The area under the ROC curve (NEDP vs. BMP) was higher for OPG (82.5, 95% CI 74.5-90.6) than for RANK-L (69.2, 95% CI 590-7940). Specificity for OPG was 87.7% (95% CI 75.7-94.2) and sensitivity was 74.1% (95% CI 60.4-85.0), both values increasing when considered together with CEA and CA15-3. For VMP, OPG and RANK-L were expressed in only one patient. Our results highlight the potentially important role of circulating OPG in the diagnosis of bone metastases. A confirmatory study on a larger case series is ongoing. Source

Korpal M.,Princeton University | Ell B.J.,Princeton University | Buffa F.M.,University of Oxford | Ibrahim T.,Osteoncology Center | And 15 more authors.
Nature Medicine | Year: 2011

Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome. © 2011 Nature America, Inc. All rights reserved. Source

Ibrahim T.,Osteoncology Center | Sacanna E.,Osteoncology Center | Gaudio M.,Pathology Unit | Mercatali L.,Osteoncology Center | And 7 more authors.
Clinical Breast Cancer | Year: 2011

Background: The RANK/RANKL/OPG system is active in primary cancers such as breast, prostate, and also in their bone metastases. CXCR4 chemokine receptor is highly expressed in human breast cancer cells and is believed to facilitate the homing of tumor cells to organs such as bone that express high levels of its ligand SDF1. Our study aimed to investigate whether the analysis of these markers with an inexpensive and simple test can help to predict bone metastases in breast cancer patients. Patients and Methods: Marker expression was evaluated by immunohistochemical staining in paraffin-embedded tissue sections of primary breast cancers from 40 individuals: 20 patients with bone metastases (BM), 10 with visceral metastases (VM; considered together as the relapsed group), and 10 with no evidence of disease (NED). Results: RANKL was not detected in tumor cells. OPG- and RANK-positive tumors are found with similar frequency in NED (20%) and in relapsed patients (23% and 17%, respectively). However, in the latter subgroup, only RANK positivity was always associated with bone relapse. The frequency of CXCR4-positive tumors was three-fold higher in relapsed (30%) than in NED (10%) patients and positivity was always linked to bone metastases. Considering NED and VM patients together versus BM patients, we observed that CXCR4 expression, alone (P =.008) or in combination with RANK (P <.001), identified patients destined to relapse to bone. Conclusion: Our results provide the first clinical evidence to support a pivotal role of combined CXCR4 and RANK expression in predicting bone relapse. © 2011 Elsevier Inc. All rights reserved. Source

Chakrabarti R.,Princeton University | Chakrabarti R.,State University of New York at Buffalo | Hwang J.,Princeton University | Andres Blanco M.,Princeton University | And 16 more authors.
Nature Cell Biology | Year: 2012

The epithelial-mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer. © 2012 Macmillan Publishers Limited. Source

Ibrahim T.,Osteoncology Center | Farolfi A.,Osteoncology Center | Scarpi E.,Unit of Biostatistics and Clinical Trials | Mercatali L.,Osteoncology Center | And 5 more authors.
Oncology (Switzerland) | Year: 2013

Objective: As hormone receptor and human epidermal growth factor receptor-2 (HER-2) expression in primary breast tumors frequently differs from that of paired metastases, we first evaluated the discordance rate (DR) of estrogen receptor (ER), progesterone receptor (PgR), HER-2, and Ki67 in breast cancer patients and then assessed the discordance effect on prognosis. Methods: Of 145 cases reviewed, 120 with samples available from both primary tumors and paired metastases were included in the study. For each receptor, the DR was calculated as the proportion of discordant cases with respect to the total number of patients. Results: A change in ER status was observed in 19 cases (DR 16.4%), while PgR status was modified in 48 cases (DR 41.7%). HER-2 was altered in 21 cases (DR 17.5%), and Ki67 in 33 patients (DR 38.8%). Patients with Ki67 <20% had a significantly higher postrecurrence survival (PRS) compared to patients with Ki67 ≥20% (p = 0.0006). Patients with ER-positive tumors showed a trend towards higher PRS (p = 0.064) compared to ER-negative patients. No differences in PRS were seen among patients with altered PgR or HER2 status. Conclusions: Changes in the cell biology of breast cancer metastasis would seem to occur and biopsy could potentially guide the choice of treatment and provide useful information on prognosis. Copyright © 2012 S. Karger AG, Basel. Source

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