The Effects of Various Chemical Factors on Prostate Tumor Cells of Cx43 and the Significance of the Cancer Treatment
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Prostate cancer is a common cancer disease within older male populations and its incidence rate increased year by year. The abnormal exception of connexon is one of its pathogenesis. Researches show that Cx43 expression in prostate cancer was effectively lower compared with prostate epi- thelial, what's more, there existed a gap junctional intercellular communication defects in pros- tate cancer. So, Cx43 expression defects may significantly affect the prostate cancer process. Re- searches also show that tea polyphenols substances, selenium substances, hormone-like sub- stances, vitamins, alkaloids, and other chemical substances are also have different levels of effects on the expression of Cx43 in prostate tumor cells. Therefore, they also influenced the development of prostate cancer. So, the following article will mainly state the effecting of variety chemical fac- tors on Cx43 in prostate cancer cells and therapeutic implications.Keywords:
Pathogenesis
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Breast cancer is a major challenge to current medicine; it is the disease with highest death rate in the female population and is even of significance to the male population. Although breast cancer is effectively treated by surgery at early stages, patients who present with breast cancer metastases at diagnosis or who subsequently develop metastatic disease have a much poorer prognosis. A feature of the normal breast endothelium is its regulation by the endocrine system; steroid hormones such as oestrogen are released predominantly by the ovary and control both proliferation and differentiation of epithelial cells. The proliferation of corresponding carcinoma cells that arise in early breast cancer has a similar dependence on endocrine hormones. Thus, one of the main methods for treating early breast cancer, apart from surgery, is to block the growth promoting action of oestrogen, either by blocking the downstream action with antioestrogens such as tamoxifen or by reducing the concentration of circulating oestrogen through oophorectomy or treatment with aromatase inhibitors. While such treatment is generally effective, the consequent emergence of aggressive tumours is common and poses a major barrier to successful disease management. Heterogeneity has been postulated to be a key property of both breast cancer and epithelial subtypes of normal breast tissue (Visvader, 2009). MCF-7, a commonly used breast cancer cell line, has been propagated for many years by multiple groups and it might be expected that such propagation would select a single phenotype that had the highest growth rate. However, the finding of extensive heterogeneity among MCF-7 lines used by different groups (Nugoli et al., 2003) suggests that mechanisms may be operating within proliferating MCF-7 populations to generate phenotypic diversity continuously. The aim of this chapter is to discuss the evidence of the way that the MCF-7 breast cancer cell line is heterogeneous with respect to both the expression of hormone receptors and to the utilization of the signalling pathways linked to these receptors. Such heterogeneity may be reflected by the presence of multiple phenotypes within a tumour population that differ markedly in their relative expression of receptors such as progesterone receptor (PR), oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and epidermal growth factor receptor-2 (HER2; also known as ErbB2).
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Abstract A128 Breast cancer is the most frequent cancer in women with over 40,000 deaths per year in the United States. The prognosis for a subset of these women with breast tumors that are either estrogen receptor (ER)-negative or ER- and overexpress ErbB2 (also known as HER2/Neu) is very poor because these tumor are aggressive and do not respond to standard treatments. This situation emphasizes the importance of developing new agents and protocols for preventing breast cancer. Numerous epidemiological studies suggest that plant-based diets are protective against many types of cancer. However, there is very little known about many of these botanicals for preventing breast cancer. Nexrutine is an herbal extract from the Chinese tree phellodendron amurense that has been used over hundreds of years in traditional Chinese medicine for treatment of inflammation, gastroenteritis, abdominal pain, and diarrhea. Numerous studies indicate a relationship between inflammation and cancer. In particular, many studies have reported that breast tumors have increased expression of cyclooxygenase (COX-2), the rate-limiting enzyme that controls the conversion of arachidonic acid into pro-inflammatory prostaglandins (PG). High levels of PGE2 in breast tumors are associated with increased proliferation, metastasis, resistance to apoptosis, and angiogenesis. Overexpression of COX-2 occurs more frequently in DCIS, which suggests that COX/PG is an important target for preventing the progression of DCIS to metastic breast cancer. However, considering the recent concerns of the cardiovascular risks associated with the COX-2 inhibitor drugs, there is an urgent need to develop nontoxic approaches to target the PGE pathway. Targeting PGE2 synthese and 15-hydroxy PG dehydrogenase (15-PGDH) provides an alternative strategy to block PGE2 without the risk the cardiovascular risks. SkBr3, MDA-MB 231, and BT474 cells were treated with nexrutine for 24, 48, and 72 h. Nexrutine produced a time and concentration decrease in cell survival, which was accompanied by a G0/G1 cell cycle arrest and decreased protein expression of cyclin D1. nexrutine reduced the production of PGE2 without altering PGI2. The reducing in PGE2 levels was associated with decreased protein expression of PGE2 synthase and increased 15-PGDH. Peroxisome proliferators-activated receptor (PPAR) γ is also increased in many cancers including breast. Recent studies have suggested that PPAR γ may function as a tumor promoter gene. Upregulation of PPAR γ has been demonstrated in ER- breast cancer tumors and may be a marker for reoccurrence of DCIS. We show that nexrutine decreased activation of PPAR γ. Nexrutine reduced protein levels of PPAR γ and activation of PPAR γ. Growth inhibitory effects of nexrutine were associated with increased PTEN and Beclin 1 protein expression, and type-2 cell death known as autophagy. Based upon these findings, we propose that the use of nexrutine could provide a novel approach for protection against breast cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A128.
Cancer Prevention
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Breast cancer is the second most common malignancy in Indian women. Among the members of the steroid receptor superfamily the role of estrogen and progesterone receptors (ER and PR) is well established in breast cancer in predicting the prognosis and management of therapy, however, little is known about the clinical significance of androgen receptor (AR) in breast carcinogenesis. The present study was aimed to evaluate the expression of AR in breast cancer and to elucidate its clinical significance by correlating it with clinicopathological parameters, other steroid receptors (ER and PR) and growth factors receptors (EGFR and CD105).Expression of AR, ER, PR, epidermal growth factor receptor (EGFR) and endoglin (CD105) was studied in 100 cases of breast cancer by immunohistochemistry (IHC). Risk ratio (RR) along with 95% confidence interval (CI) was estimated to assess the strength of association between the markers and clinicopathological characteristics. Categorical principal component analysis (CATPCA) was applied to obtain new sets of linearly combined expression, for their further evaluation with clinicopathological characteristics (n=100).In 31 cases presenting with locally advanced breast cancer (LABC), the expression of AR, ER, PR, EGFR and CD105 was associated with response to neoadjuvant chemotherapy (NACT). The results indicated the association of AR+ (P=0.001) and AR+/EGFR- (P=0.001) with the therapeutic response to NACT in LABC patients. The AR expression exhibited maximum sensitivity, specificity and likelihood ratio of positive and negative test. The present results showed the benefit of adding AR, EGFR and CD105 to the existing panel of markers to be able to predict response to therapy.More studies on the expression profiles of AR+, AR+/CD105+ and AR+/EGFR- in larger set of breast cancer patients may possibly help in confirming their predictive role for therapeutic response in LABC patients.
Steroid hormone receptor
Steroid hormone
Sex steroid
Progesterone receptor
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Abstract : Epidemiological evidence has demonstrated an inverse association between serum vitamin D levels and sunlight exposure to prostate cancer incidence. In addition, serum androgen levels and biologically available testosterone decrease significantly in elder men while the incidence rate of prostate cancer increases. These findings lead to the hypothesis that androgen- and vitamin D-mediated signaling events may act together to inhibit prostate tumor initiation and/or development. Using concurrent microarray analyses, we demonstrated that testosterone and 1,25(OH)2D3 co-operate to regulate mRNA and miRNA expression, including some well-defined oncogenes and tumor suppressor genes. Pheno typically, this results in G0/G1 cell cycle arrest and increased neutral lipid accumulation in LNCaP cells, as a consequence of repression of various cell cycle regulators and the up-regulation of PPAR alpha; respectively. This suggests that the cross talk between T and 1,25(OH)2D3 induces cell cycle arrest and promotes cell differentiation in LNCaP cells. It is important ton ote that co-treatment of LNCaP cells with testosterone, 1,25(OH)2D3 and other standard therapeutics, including bicalutamide, docetaxel and TRAIL did not affect the potencies of these treatments, though there were no synergistic effects either. This suggests that androgen andvitamin D supplementation slow disease progression without affecting the efficacy of standard therapies for prostate cancer. Further analysis is still required to elucidate the underlying mechanisms of T and 1,25(OH)2D3 to modulate key mRNA and miRNA and their significance in prostate tumorigenesis and therapeutic interventions.
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Abstract Estrogen receptors (ERs) are known to play an important role in the proper development of estrogen-sensitive organs, as well as in the development and progression of various types of cancer. ERα, the first ER to be discovered, has been the focus of most cancer research, especially in the context of breast cancer. However, ERβ expression also plays a significant role in cancer pathophysiology, notably its seemingly protective nature and loss of expression with oncogenesis and progression. Although ERβ exhibits antitumor activity in breast, ovarian, and prostate cancer, its expression is associated with disease progression and worse prognosis in lung cancer. The function of ERβ is complicated by the presence of multiple isoforms and single nucleotide polymorphisms, in addition to tissue-specific functions. This mini-review explores current literature on ERβ and its mechanism of action and clinical implications in breast, ovarian, prostate, and lung cancer.
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Neoplastic transformation
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A11 High prevalence and poor prognosis of prostate cancer in African Americans has been associated with high intake of saturated fats and cholesterol. The connection between obesity, dietary fat and aggressive prostate cancer is inferred from several retrospective and prospective studies of populations, animal experiments and limited clinical research on humans. The pathogenesis of prostate cancer by obesity is unclear and controversial. Nevertheless, lipid abnormalities, especially elevated circulating cholesterol, triglycerides and LDL cholesterol are common features of obesity and may be the contributing factors. The pathogenic mechanism for promotion of prostate cancer by cholesterol is unclear. Several studies show that cellular cholesterol trafficking favors it’s mixing with the bulk plasma membrane cholesterol. Membrane cholesterol enrichment is reportedly a trigger of signaling responses leading to cell growth and carcinogenesis. To the contrary, dietary phytosterols, which are plant cholesterol counterparts, have reportedly suppressive effects on cell growth and signaling. The objective of this study was to establish the molecular mechanism for sterol regulation of prostate cancer incidence and probably the basis for racial disparity in incidence of disease. We investigated the hypothesis that the differences in sterol promotion of prostate cancer can be attributed to differential signaling of caveolin1 (cav-1)-mediated oncogenes and growth-suppressors. The expression of these genes in cultured prostate cancer cell lines was genetically analyzed by RT-PCR. The effects of different sterols on prostate cell growth were analyzed with a Coulter counter, while mitosis and apoptosis were assayed by real RT-PCR and flow cytometry. Our study revealed that cholesterol enrichment promoted mitosis and cell growth, while phytosterols suppressed mitosis and significantly induced tumor-suppression and promoted apoptosis. We demonstrated for the first time that cholesterol upregulated the expression of an oncogene PCGEM1 even in androgen-insensitive prostate cancer cell lines. Phytosterols reversed this effect, while upregulating the expression of cav-1, a mediator of androgen-dependent proto-oncogene signals that control growth and apoptosis. Cholesterol also attenuated the co-expression of cav-1 and NDRG1 genes in both prostate cancer cell lines, while phytosterols reversed this effect. Similarity in the pattern of expression of cav-1 with oncogenes and growth-suppressors by these sterols suggests that cav-1 may mediate various signals of sterol-enrichment. Sterols may therefore contribute to the disparity in incidence of prostate cancer among racial groups by molecular mechanisms that involve cav-1 signaling of pro- and anti-apoptotic genes.
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Epidemiological data have indicated that there are some sex-related differences in bladder cancer. Indeed, the incidence of bladder cancer in men has been substantially higher than that in women throughout the world, while women tend to have higher stage disease and poorer prognosis. These gender disparities have prompted to investigate sex hormones and their cognitive receptors in bladder cancer. Specifically, estrogen receptors, including estrogen receptor-α and estrogen receptor-β, have been shown to contribute to urothelial carcinogenesis and cancer progression, as well as to modulating chemosensitivity in bladder cancer, although conflicting findings exist. Meanwhile, immunohistochemical studies in surgical specimens have assessed the expression of estrogen receptors and related proteins as well as its associations with clinicopathologic features of bladder cancer and patient outcomes. This review article summarizes and discusses available data indicating that estrogen receptor signaling plays an important role in urothelial cancer.
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Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006
B73
Genetic, epigenetic, and environmental factors influence tumor development and progression. Environmental factors, such as exposure to radiation and carcinogens, increase the risk of cancer by causing genetic mutations. A lesser understood, but widely implicated, risk factor for cancer is certain lifestyles related to diet. Short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are relatively high in caloric content and its levels of SCFAs in blood and other parts of the body can be influenced by diet such as alcohol consumption and by infections. Recently, two orphan G-protein coupled receptors, GPR41 and GPR43, have been identified as novel receptors for SCFAs, with propionate as the most potent agonist. Through RT-PCR and immunocytochemistry, we demonstrated that prostate cancer cells expressed GPR43, and to much less extent, GPR41. Immunohistochemical staining for GPR43 indicated that most normal prostate glands showed focal and weak staining. Increased expression was observed in high grade prostatic intraepithelial neoplasia. Most prostatic adenocarcinoma showed variable cytoplasmic staining. Higher expression of GPR43 was noted in some high grade tumors. Treatment of PC-3 or LNCaP cells with SCFAs, especially propionate, suppressed apoptosis and promoted survival of prostate cancer cells in the absence of serum trophic factors. Further, we found that SCFAs decreased the adhesion of prostate cancer cells toward fibronectin and stimulated the migration of prostate cancer cells under serum free conditions. Our data suggest that prostate cancer cells express a novel membrane receptor for SCFAs and that SCFAs exert pleiotrophic effects on prostate tumor cell survival, adhesion, and motility.
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