#4068 Background: Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and are known to be involved in the development of bone metastasis from solid tumours. Recent studies have shown that BMP-10 plays some critical roles during the fetal or postnatal development, particularly during the morphogenesis of heart. However, its role in cancer is largely unknown. The present study investigated the role of BMP-10 in breast cancer cells and pattern of expression in clinical breast cancers.
 Methods: The expression of BMP-10 was examined in a cohort of human breast cancer specimen (normal, n=23; cancer, n=97), using both quantitative real time PCR and immunohistochemical staining. Levels of BMP-10 transcripts were correlated with clinical and pathological, together with clinical outcome information of the patients. A human BMP-10 expression construct was used to transfect breast cancer cells (MDA-MB-231, negative in BMP-10 expression). The expression of BMP-10 in the transfected cells was verified using RT-PCR and western blot. The effect of BMP-10 expression on growth of MDA-MB-231 cells was investigated using an in vitro growth assay.
 Results: Immunohistochemical staining revealed a decreased protein expression of BMP-10 in breast cancer cells, compared with normal mammary epithelial cells. The quantitative real time PCR further demonstrated that low levels of the BMP-10 transcripts correlated to poor prognosis. Tumours form patients with good prognostic index (NPI<3.4) had significantly higher levels of BMP-10 transcripts, compared with those from poor prognostic index (NPI>5.4) (p=0.045). In addition, patients who died of breast cancer showed a significantly lower levels of the transcript compared with those who remained disease free (p=0.027). Mean disease free survival of the patients with higher level of BMP-10 was 132.8 (122.0-143.5, 95% CI) months, which was significantly longer compared to 93.7 (60.3-127.2) months of patients with lower level of BMP-10 expression, p=0.043 using Kaplan-Meirer survival analysis. An inhibitory effect on cell growth by over-expression of BMP-10 was seen in the breast cancer cells. The absorbance of MDA-MB-231 BMP-10 over-expressing (MDA-MB-231BMP-10exp) cells of Day 5 is 1.40±0.19, p<0.01 vs both MDA-MB-231 wild type (MDA-MB-231WT, 2.17±0.11) and empty vector control (MDA-MB-231pEF/His, 1.83±0.17).
 Conclusions: Taken together, BMP-10 can inhibit the cell growth of breast cancer cells. A decrease in BMP-10 expression correlates with poor prognosis of patients with breast cancer. BMP-10 may function as tumor suppressor in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4068.
Background: There is a significant body of in vitro evidence and pre-clinical data which demonstrates that aspirin inhibits the growth of tumours and prevents the development of metastases[1]. A recent meta-analysis using individual patient data from randomized trials evaluating the cardiovascular effects of aspirin reports a reduction in cancer deaths after 5 years (hazard ratio 0.46, 95% confidence interval 0.27-0.77)[2]. Effects on risk of metastases and death following a cancer diagnosis have also been observed[3]. An analysis of the Nurses’ Health Study found that aspirin use following a diagnosis of stage I-III breast cancer was associated with a lower risk of breast cancer death (for those taking aspirin 2-5 times per week, relative risk 0.27, 95% confidence interval 0.15-0.47)[4]. Concerns over toxicity have limited the use of aspirin as a primary prevention agent against cancer. In the adjuvant setting the benefit:risk ratio will be different with higher morbidity and mortality from recurrent cancer potentially outweighing the risks associated with regular aspirin use. The Add-Aspirin trials will investigate whether regular aspirin use after curative treatment for localised malignancy can prevent tumour recurrence and prolong survival. As an inexpensive drug with a potential therapeutic role in several common cancers, aspirin could have a huge impact on the global cancer burden. Trial design: Multicentre, international, phase III, double-blind, placebo-controlled randomized trial in patients with early breast cancer. Participants will be randomised to enteric-coated aspirin 100mg, aspirin 300mg or matching placebo daily for at least 5 years. Parallel trials based on a common infrastructure will be conducted in colorectal, gastro-oesophageal and prostate cancer. Eligibility criteria: Patients who have undergone primary therapy, including curative surgery and appropriate neoadjuvant/adjuvant therapies for histologically confirmed invasive breast cancer which is node positive or node negative with high-risk features. Patients who have already participated in other primary treatment trials may be eligible subject to agreement from the trial management groups. Specific aims: The primary outcome will be disease-free survival. Secondary endpoints include overall survival, toxicity, cardiac morbidity and assessment of overall healthcare benefits. Translational work will investigate mechanisms of action and biomarkers for toxicity and treatment efficacy (including PIK3CA mutation status and COX-2 expression). Statistical methods: Approximately 3100 patients will be needed to test for a 4% improvement in DFS associated with aspirin use. [1] Langley RE et al. Br J Cancer. 2011;105(8):1107-13. [2] Rothwell PM et al. Lancet. 2011;377(9759):31-41. [3] Rothwell PM et al. Lancet. 2012;379(9826):1591-601. [4] Holmes MD et al. J Clin Oncol 2010;28(9):1467-72. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-4-01.
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