Background and aim: Atypical small acinar proliferation (ASAP) is defined as atypical foci suspicious for but not diagnostic of malignancy. ASAP is known as a strong predictive factor associated with prostate cancer. Because the diagnostic criteria for ASAP are subjective, objective diagnostic criteria were applied for ASAP as follows: (i) total loss of basal cells confirmed by immunohistochemistry and inconspicuous nucleoli; and (ii) a minute (≤500 micrometer in length) focus of atypical glands with total loss of basal cells and prominent nucleoli. Methods: To evaluate the cancer detection rate of ASAP diagnosed by objective diagnostic criteria, 114 patients initially diagnosed with ASAP were reviewed. Results: ASAP was noted in 2.17% of prostate biopsy cases. Eighty‐one patients were successfully followed up. Twenty patients (24.7%) were finally diagnosed as having adenocarcinoma by subsequent biopsy. According to the criteria, we subclassified ASAP into two groups: ASAP (not otherwise specified [NOS]) and ASAP (suspicious microscopic adenocarcinoma). ASAP (NOS) and ASAP (suspicious microscopic adenocarcinoma) showed significantly different cancer detection rates (20.3% vs 71.4%) at subsequent biopsies (P= 0.003). Sixteen patients underwent radical prostatectomy, and 13 cases (81.2%) were categorized as clinically significant prostate cancer. Conclusions: The presence of ASAP in needle biopsy was evaluated to be an important predictor of cancer.
Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras. Small interfering RNA(siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express active H-Ras as well as in Hs578T breast carcinoma and T24 bladder carcinoma cells that express endogenous active mutant of H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program. Flotillin-1 was crucial for the activation of the Ras-GRF1 exchange factor and its interaction with H-Ras in lipid rafts. Using a xenograft tumor model, we show that knockdown of flotillin-1 reduces the tumor growth in vivo. Importantly, tissue microarrays of 289 breast cancer patients revealed that flotillin-1 expression in the plasma membrane positively correlates with HER2/neu expression(p<0.001) and high histologic grade(p=0.014). Although infrequent, the membranous flotillin-1 expression is significantly associated with poor disease-free survival of patients(p=0.005), suggesting the clinical importance of predicting the characteristics of a small subpopulation of malignant breast cancer. Taken together, our findings provide new insight into the molecular basis of the Ras isoform-specific signaling mechanism leading to cell invasion that depends on the lipid-based sorting platforms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4165. doi:1538-7445.AM2012-4165
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