Caspase 3 in breast cancer.
ABSTRACT An inability to undergo apoptosis is widely thought to contribute to both tumorigenesis and tumor progression. One of the key mediators of apoptosis is the thiol protease caspase 3. In this investigation, caspase 3 mRNA and protein expression in breast cancer was examined.
Caspase 3 was measured at the mRNA level using reverse transcription-PCR and at the protein level using both Western blotting and activity assays. Levels of apoptosis were determined using an ELISA, which detects nucleosomes released during DNA fragmentation.
Relative levels of caspase 3 mRNA were similar in breast carcinomas (n = 103), fibroadenomas (n = 25), and normal breast tissues (n = 6). However, levels of both the precursor and active forms of caspase 3 were significantly higher in carcinomas compared with both fibroadenomas (P = 0.0188) and normal breast tissues (P = 0.0002). Levels of apoptosis were also highest in the carcinomas and correlated significantly with active caspase 3 levels (r = 0.481; P = 0.0003). In the carcinomas, expression of caspase 3 showed no significant relationship with either tumor size, tumor grade, nodal status, or steroid receptor status but was significantly higher in ductal carcinomas than in lobular carcinomas (P = 0.0188).
We conclude that rates of apoptosis as measured by both caspase 3 activation and nucleosome release are higher in breast cancer than in nonmalignant breast tissue. This finding would appear to conflict with the widely held belief that apoptosis is reduced in malignancy. The proliferation:apoptosis ratio, however, may be higher in carcinomas than in the corresponding normal tissue.
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ABSTRACT: Oral carcinomas are known to have a greater apoptotic index than normal oral epithelium, evident as shrinking cells with condensed chromatin. In this study, these morphologically apoptotic cells stained positively for cleaved (active) caspase-3. In normal oral epithelium, cleaved caspase-3 positive-cells were only rarely detected. The terminally differentiated surface epithelial layers did not express cleaved caspase-3. The caspase-3 pro-enzyme showed a gradient of expression in normal oral epithelium, decreasing with differentiation. No expression was detectable in surface epithelial layers. Lack of expression of the major 'executioner' caspase-3 may, at least in part, explain differences in morphology between terminally differentiated and apoptotic cells. In cancers of different tissue origins, caspase-3 pro-enzyme expression can be either increased or decreased compared with normal tissue counterparts. To determine how caspase-3 expression alters during oral carcinogenesis, caspase-3 expression was compared in 39 samples of normal oral epithelium and 54 oral squamous cell carcinomas. Squamous cell carcinomas had more intense caspase-3 staining than normal epithelium (p < 0.001). Moreover, within the oral squamous cell carcinoma series, there was significantly more intense nuclear and cytoplasmic staining with increasing STNMP stage (p = 0.017 and 0.03, respectively). This was a reflection of significant associations with site (S), palpable lymph nodes (N), and differentiation (P). Both caspase-3 staining intensity and the percentage of cells positive for caspase-3 were inversely associated with differentiation. Studies of the mechanisms by which high levels of caspase-3 expression are tolerated in oral carcinoma cells may identify targets that can be used to harness caspase-3 overexpression for therapeutic benefit.
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ABSTRACT: The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate various signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process. © 2013 Wiley Periodicals, Inc.International Journal of Cancer 12/2013; · 6.20 Impact Factor
Dataset: ACTA Biologica Hungarica 2013