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Purpose of review Bisphosphonate therapy has been used as standard of care for patients with metastatic bone disease. As bisphosphonate had demonstrated antitumor effects in preclinical studies, it was natural to advance to the development of large phase 3 trials that would test the activity of bisphosphonate in the adjuvant setting. Surprisingly, the results of adjuvant breast cancer trials have shown either modest or contradictory effects. One of the most consistent results across the latest reports on this issue is that bisphosphonate shows benefit in the prevention of distant relapses in breast cancer women after menopause, but not before. We sought to comment on the most recent studies and to reflect on the possible practical recommendations for the use of bisphosphonate in this setting. Recent findings In the last San Antonio Breast Cancer Conference, the Early Breast Cancer Trialists' Collaborative Group's Bisphosphonate Working Group presented a meta-analysis of individual patient data from randomized trials. The main conclusions of this presentation were that all bisphosphonates (not only nitrogen-containing bisphosphonates) can decrease bone recurrence in postmenopausal women with early breast cancer. Summary The benefit of bisphosphonate use in an adjuvant setting is significant only in postmenopausal women. Further investigation into factors influencing the response to bisphosphonate treatment is needed. © 2014 Wolters Kluwer Health - Lippincott Williams & Wilkins. Source


Pakala S.B.,George Washington University | Rayala S.K.,University of Texas M. D. Anderson Cancer Center | Rayala S.K.,Indian Institute of Technology Madras | Wang R.-A.,University of Texas M. D. Anderson Cancer Center | And 12 more authors.
Cancer Research | Year: 2013

Overexpression of the prometastatic chromatin modifier protein metastasis tumor antigen 1 (MTA1) in human cancer contributes to tumor aggressiveness, but the role of endogenous MTA1 in cancer has not been explored. Here, we report the effects of selective genetic depletion of MTA1 in a physiologically relevant spontaneous mouse model of breast cancer pulmonary metastasis. We found that MTA1 acts as a mandatory modifier of breast-to-lung metastasis without effects on primary tumor formation. The underlying mechanism involved MTA1-dependent stimulation of STAT3 transcription through action on the MTA1/STAT3/Pol II coactivator complex, and, in turn, on the expression and functions of STAT3 target genes including Twist1. Accordingly, we documented a positive correlation between levels of MTA1 and STAT3 in publicly available breast cancer data sets. Together, our findings reveal an essential modifying role of the physiologic level of MTA1 in supporting pulmonary metastasis of breast cancer. ©2013 AACR. Source


Casimiro S.,Institute Medicina Molecular FML | Luis I.,Institute Medicina Molecular FML | Fernandes A.,Institute Medicina Molecular FML | Pires R.,Institute Medicina Molecular FML | And 6 more authors.
Clinical and Experimental Metastasis | Year: 2012

Bone is a major target for metastases in the most frequent solid tumors, which result in severe complications and are a major cause of pain. A bone metastasis gene expression signature was identified using human breast cancer cells in a mouse model. The bone metastasis-related genes encode secretory and cell surface proteins implicated in bone-homing (CXCR4), angiogenesis (CTGF and FGF5), invasion (MMP-1 and ADAMTS1), and osteoclast recruitment (IL11). This signature superimposes on the 70-gene poor prognosis gene expression signature for breast cancer, and only ADAMTS1, CTGF and IL11 were found to be overexpressed in human primary breast cancers with bone relapse. We analyzed the expression of the six bone metastasis-related genes in bone metastases from patients with different types of solid tumors, to assess its relevance in human clinical samples. MMP-1, CXCR4, FGF5 and CTGF were found to be overexpressed in tumor cells of human bone metastases when compared to a human normal epithelial cell line. All the analyzed genes were overexpressed in the tumor cells of breast cancer bone metastases when compared to normal breast tissue. We did not detect any differences between the expression of these genes in bone metastases from breast cancer or from other types of solid tumors. Importantly, there was a significant correlation between the expressions of IL11/CTGF, IL11/ADAMTS1, CTGF/CXCR4, CTGF/ADAMTS1, and MMP-1/ADAMTS1, supporting the cooperative function of these proteins in the bone microenvironment, and the potential functional role of these genes in the establishment of bone metastases in vivo. © 2011 Springer Science+Business Media B.V. Source

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