CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes. [Cancer Res 2008;68(12):4580-7]

BackgroundDespite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor.MethodsIn this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated.ResultsIn phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib.ConclusionIL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC.Trial registrationClinicalTrials.gov Identifier: NCT00389285

A 68-year-old white female presented with two years of progressively worsening dyspnea. Echocardiography revealed a large right atrial mass and partial obstruction of the inferior vena cava. Further imaging revealed a cystic dense mass in the inferior vena cava and right atrium. Immunohistochemical stains were consistent with leiomyosarcoma. Intraoperatively, the tumor was noted to originate from the posterior aspect of the inferior vena cava. The patient underwent successful resection of the mass. Adjuvant radiation therapy was completed. The patient's dyspnea gradually improved and she continues to remain disease free five years post-resection.

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Worldwide disparities exist between geographic regions with regard to prostate cancer incidence and mortality. Countries in East Asia have lower rates of prostate cancer compared with Western countries such as Canada and the US. Some suggest that dietary differences between the two geographic regions, particularly the higher amount of phytoestrogens consumed in East Asia, is responsible for the difference in prostate cancer incidence. The mechanism of action of the soy isoflavones is incompletely understood, but in regards to prostate carcinogenesis likely involves estrogenic effects, cell cycle inhibition, anti-angiogenesis and induction of apoptosis. Recent clinical studies have provided mixed results with regard to a clear association between prostate cancer and soy consumption. Further studies are needed to understand more clearly the relationship between soy consumption and prostatic diseases.