Can a single model explain both breast cancer and prostate cancer?

<p>Abstract</p> <p>Background</p> <p>The Estradiol-Dihydrotestosterone model of prostate cancer (PC) showed how the interaction of hormones with specific hormone receptors affected apoptosis. The same hormone can produce different effects, depending on which hormone receptor it interacts with.</p> <p>Model</p> <p>This model proposes that the first step in the development of most PC and breast cancer (BC) occurs when aromatase converts testosterone to estradiol (E2). A sufficiently high enough local level of E2 results in telomerase activity. The telomerase activity allows cell division and may lead to BC or PC, which will proliferate if the rate of cell division is greater than the rate of cell death. The effect of hormones on their hormone receptors will affect the rate of cell death and determine whether or not the cancer proliferates.</p> <p>Conclusion</p> <p>By minimizing bcl-2 and maximizing apoptotic proteins, new systemic treatments for BC and PC can be developed that may be more effective than existing treatments.</p

Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs), some of which function as oncogenes or tumor suppressor genes, are involved in carcinogenesis via regulating cell proliferation and/or cell death. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor. miR-34 targets Notch, HMGA2, and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells. The role of miR-34 in gastric cancer has not been reported previously. In this study, we examined the effects of miR-34 restoration on p53-mutant human gastric cancer cells and potential target gene expression.</p> <p>Methods</p> <p>Human gastric cancer cells were transfected with miR-34 mimics or infected with the lentiviral miR-34-MIF expression system, and validated by miR-34 reporter assay using Bcl-2 3'UTR reporter. Potential target gene expression was assessed by Western blot for proteins, and by quantitative real-time RT-PCR for mRNAs. The effects of miR-34 restoration were assessed by cell growth assay, cell cycle analysis, caspase-3 activation, and cytotoxicity assay, as well as by tumorsphere formation and growth.</p> <p>Results</p> <p>Human gastric cancer Kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. Bcl-2 3'UTR reporter assay showed that the transfected miR-34s were functional and confirmed that Bcl-2 is a direct target of miR-34. Restoration of miR-34 chemosensitized Kato III cells with a high level of Bcl-2, but not MKN-45 cells with a low level of Bcl-2. miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth.</p> <p>Conclusion</p> <p>Our results demonstrate that in p53-deficient human gastric cancer cells, restoration of functional miR-34 inhibits cell growth and induces chemosensitization and apoptosis, indicating that miR-34 may restore p53 function. Restoration of miR-34 inhibits tumorsphere formation and growth, which is reported to be correlated to the self-renewal of cancer stem cells. The mechanism of miR-34-mediated suppression of self-renewal appears to be related to the direct modulation of downstream targets Bcl-2, Notch, and HMGA2, indicating that miR-34 may be involved in gastric cancer stem cell self-renewal/differentiation decision-making. Our study suggests that restoration of the tumor suppressor miR-34 may provide a novel molecular therapy for p53-mutant gastric cancer.</p

Cell proliferation and apoptosis in prostate cancer: significance in disease progression and therapy

Recent biochemical and genetic studies have substantially increased our understanding of death signal transduction pathways, making it clear however, that apoptosis is not a single-lane, one-way street. Rather, multiple parallel pathways have been identified. For instance, analysis of bcl-2, bax, p53, and caspase knockout mice while establishing distinct roles for each of these apoptotic players, they also provided valuable information for the design of specific inhibitors of apoptosis. Thus blocking one pathway, as in caspase knockout mice, what we observe is not a complete suppression of apoptosis but rather a delay in apoptosis induction (Hakem et al., 1998; Kuida et al., 1998). In view of nature's means of ensuring activation of a compensatory apoptotic response, when one pathway fails in developing prostate cancer therapeutic interventions, the challenge remains to further dissect individual apoptotic pathways. Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death, clearly suggest that effective prostate cancer therapies are not only molecularly targeted, but that are also customized to take into account the delicate balance of opposing growth influences in the ageing gland. In this review we discuss the evidence on the significance of molecular deregulation of the key players of this growth equlibrium, apoptosis and cell proliferation in prostate cancer progression, and the clinical implications of changes in the apoptotic response in disease detection and therapy