裸鼠乳腺癌的超声研究

目的研究裸鼠乳腺癌的超声表现特点,为人乳腺癌的超声诊断提供有效依据。方法采用MCF-7细胞株建立裸鼠乳腺癌瘤模型,待原位移植后第23天用超声观察其图像的特点,并与人乳腺癌的特点进行对比分析。结果裸鼠乳腺癌平均大小7.4mm×5.6mm;椭圆形,内部低回声,分布均匀,境界清晰和尚清晰;并与人乳腺癌之特点有许多不同。结论裸鼠乳腺癌的生长仅23天,而人乳腺癌的生长数月至数年,两者图像之特点有许多不同。对<10mm或很早的原位癌超声缺乏特征性指标而易误诊为良性肿瘤。     

Suppression of Implanted MDA-MB 231 Human Breast Cancer Growth in Nude Mice by Dietary Walnut

Walnuts contain components that may slow cancer growth including omega 3 fatty acids, phytosterols, polyphenols, carotenoids, and melatonin. A pilot study was performed to determine whether consumption of walnuts could affect growth of MDA-MB 231 human breast cancers implanted into nude mice. Tumor cells were injected into nude mice that were consuming an AIN-76A diet slightly modified to contain 10% corn oil. After the tumors reached 3 to 5 mm diameter, the diet of one group of mice was changed to include ground walnuts, equivalent to 56 g (2 oz) per day in humans. The tumor growth rate from Day 10, when tumor sizes began to diverge, until the end of the study of the group that consumed walnuts (2.9 ± 1.1 mm³/day; mean ± standard error of the mean) was significantly less (P > 0.05, t-test of the growth rates) than that of the group that did not consume walnuts (14.6 ± 1.3 mm ³ /day). The eicosapentaenoic and docosahexaenoic acid fractions of the livers of the group that consumed walnuts were significantly higher than that of the group that did not consume walnuts. Tumor cell proliferation was decreased, but apoptosis was not altered due to walnut consumption. Further work is merited to investigate applications to cancer in humans.     

Effect of Germinated Soy Protein on the Growth of HeLa Cervical Cancer Cells in Female Athymic Mice

Previous studies showed that germination could improve the antiproliferative effect of soy protein on cervical cancer cells and that a peptide fraction (MAPF) from germinated soybeans decreases the expression of PTTG1 and TOP2A (2 genes considered as therapeutic targets) causing apoptosis of cancer cells. The aim of this work was to study the effect of feeding germinated soybean protein diets on the tumor growth in nude mice inoculated with cervical cancer cells and identify the bioactive component. Mice were randomly assigned to 1 of the 6 dietary groups based in AIN-93G formulation with 6 protein sources: casein, ungerminated soy protein (SP), and SP from 2 and 6 days of germination, with and without ethanol-soluble phytochemicals (ESPC). Compared with casein-fed controls, the tumor volumes after 5 wk were reduced by 44.6% by ungerminated SP, 98.9% by 2-day-germinated SP, 97.7% by 2-day-germinated SP without ESPC, 94.7% by 6-day-germinated SP, and 92.7% by 6-day-germinated SP without ESPC (P < 0.05). Liquid chromatography coupled with tandem mass spectrometry analysis of MAPF showed that the bioactive peptide might be the leginsulin, a peptide involved in signal transduction of soybean cells. Germination is a simple procedure that could help to increase the anticancer activity of soy protein probably through generation of biologically active peptides.     

beta-Sitosterol, beta-Sitosterol Glucoside, and a Mixture of beta-Sitosterol and beta-Sitosterol Glucoside Modulate the Growth of Estrogen-Responsive Breast Cancer Cells In Vitro and in Ovariectomized Athymic Mice

We hypothesized that the phytosterols beta-sitosterol (BSS), beta-sitosterol glucoside (BSSG), and Moducare (MC; BSS:BSSG = 99:1) could modulate the growth of estrogen-dependent human breast cancer cells in vitro and in vivo. The present study evaluated the estrogenic and antiestrogenic effects of BSS, BSSG, and MC (0.001 to 150 micromol/L) on the proliferation of Michigan Cancer Foundation 7 (MCF-7) cells in vitro. Both BSS (>1 micromol/L) and MC (>50 micromol/L) increased MCF-7 cell proliferation. Treatment with 150 micro mol/L of BSS and MC increased cell growth by 2.4 and 1.5 times, respectively, compared to the negative control (NC) group. However, BSSG had no effect at the concentrations tested. The effects of dietary BSS, BSSG, and MC on the growth of MCF-7 cells implanted in ovariectomized athymic mice were also evaluated. Estrogenic effects of the phytosterols were evaluated in the NC, BSS, BSSG, and MC treatment groups, and antiestrogenic effects were evaluated in the 17 beta-estradiol (E(2)), E(2) + BSS, E(2) + BSSG, and E(2) + MC treatment groups. Mice were treated with dietary BSS (9.8 g/kg AIN93G diet), BSSG (0.2 g/kg diet), or MC (10.0 g/kg diet) for 11 wk. Dietary BSS, BSSG, and MC did not stimulate MCF-7 tumor growth. However, dietary BSS, BSSG, and MC reduced E(2)-induced MCF-7 tumor growth by 38.9% (P < 0.05), 31.6% (P = 0.08), and 42.13% (P < 0.05), respectively. The dietary phytosterols lowered serum E(2) levels by 35.1, 30.2, and 36.5% in the E(2) + BSS, E(2) + BSSG, and E(2) + MC groups, respectively (P < 0.05), compared to that of the E(2) treatment group. Estrogen-responsive pS2 mRNA expression in tumors did not differ among groups, but expression of the antiapoptotic marker B-cell lymphoma/leukemia-2 (bcl-2) in tumors from the E(2) + MC group was downregulated, compared to that of the E(2) treatment group. In summary, BSS and MC stimulated MCF-7 cell growth in vitro. Although BSSG comprises only 1% of MC, BSSG made MC less estrogenic than BSS alone in vitro. However, dietary BSS and MC protected against E(2)-stimulated MCF-7 tumor growth and lowered circulating E(2) levels.     

The Inhibitory Efficacy of Methylseleninic Acid Against Colon Cancer Xenografts in C57BL/6 Mice

Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo. We tested the hypothesis that oral dosing methylseleninic acid (MSeA), a methylselenol precursor, inhibits the growth of colon cancer xenografts in C57BL/6 mice fed a Se adequate diet. In this study, MSeA supplementation was given by an oral dose (0, 1, or 3 mg/kg body weight) regimen. MSeA increased Se content of liver, kidney, muscle, stomach (w/intestine) and plasma, and elevated blood glutathione peroxidase (GPx) activities. However, MSeA did not change lean/fat body composition, food consumption, levels of plasma leptin/adiponectin, and body weight gain. MSeA (3 mg/kg body weight) inhibited tumor growth up to 61% when compared to the control group, and this inhibition was associated with a reduction of plasma tumor necrosis factor (TNFα)/interleukin 6 (IL6) level but elevated blood GPx activities. In addition, MSeA (1 mg/kg body weight) increased the activation of caspase-3, a major apoptotic enzyme, in tumor tissues. Taken together, our MSeA oral dosing regimen was at safe levels; and high blood GPx activities, caspase-3 activities in tumor tissue and a reduction of plasma TNFα/IL6 level, play critical roles in inhibiting colon tumor growth in an immune-competent C57BL/6 mouse model.     

Lignans are accessible to human breast cancer xenografts in athymic mice

Lignan-rich diet has been linked with reduced breast cancer risk, and experimental studies have supported the hypothesis of lignans as cancer growth inhibiting compounds. However, it has not been clear if these compounds are accessible in the mammary tumor tissue in vivo. In this study, the accessibility and accumulation of lignans to breast cancer tissue was determined after oral administration of tritium labeled dietary lignan secoisolariciresinol diglucoside (3H-SDG) to athymic mice bearing MCF-7 tumors. The 3H-SDG administration increased tumor tissue radioactivity to the level similar to that in brain, skin, spleen, kidney, uterus, and lungs. The tumor tissue radioactivity was up to 92% of that found in serum, with the highest concentrations found in small (< 0.5 g) tumors. Accessibility of lignans to tumor tissue suggests that part of the anticancer activity of lignans may be due to their direct local effects on the breast cancer tissues.     

Stearate Preferentially Induces Apoptosis in Human Breast Cancer Cells

Stearic acid (stearate) is an 18-carbon saturated fatty acid that has been shown to inhibit invasion and proliferation and induce apoptosis in various human cell types. The specificity of stearate-induced apoptosis for cancerous versus noncancerous breast cells has not been examined, and the mechanism underlying stearate-induced apoptosis is unknown. Morphological analysis, cell viability, and caspase-3 activity assays demonstrated that stearate activated apoptosis preferentially in cancerous breast cells in a time- and dose-dependent manner. Inhibition of de novo diacylgycerol synthesis or protein kinase C (PKC) blocked stearate-induced caspase-3 activity, indicating the involvement of a novel or classical PKC isozyme. To our knowledge this is the first study showing that stearate induces apoptosis preferentially in breast cancer cells and implicates protein kinase C in the signaling cascade. These results raise the possibility of dietary stearate having a beneficial role in the prevention or treatment of breast cancer.     

Dietary Flaxseed Interaction With Tamoxifen Induced Tumor Regression in Athymic Mice With MCF-7 Xenografts by Downregulating the Expression of Estrogen Related Gene Products and Signal Transduction Pathways

Our previous short-term study has shown that 10% flaxseed (FS) inhibits the growth of human estrogen dependent estrogen receptor positive breast tumors (MCF-7) xenografts in ovariectomized (OVX) athymic mice and enhances the tumor inhibitory effect of tamoxifen (TAM). This study determined the long-term effect of 5% and 10% FS, with or without TAM, on the growth of MCF-7 xenografts in athymic mice and the potential mechanisms of actions. OVX mice with established MCF-7 tumors were treated with basal diet (control), 5% FS (5FS), 10% FS (10FS), and TAM (5 mg/pellet, 60-day release), alone or in combination, for 16 wk without estrogen supplementation. Tumor growth was monitored weekly. At sacrifice, the tumors were analyzed by immunohistochemistry for cell proliferation, apoptosis, and expression of estrogen-related genes and signal transduction pathways. Both 5FS and 10FS regressed the pretreatment tumor size by over 90% similar to control. TAM initially regressed the tumors but then induced a regrowth; thus, only a final 6% reduction from pretreatment tumor size was achieved, which was attenuated by combining TAM with 10FS but not with 5FS. TAM combined with 10FS regressed tumors to 55% of pretreatment tumor size due to decreased cell proliferation and increased apoptosis. The expressions of cyclin D1, estrogen receptor α, human epidermal growth factor receptor 2, and insulin-like growth factor I receptor in the TAM group were significantly reduced when TAM was combined with 5FS or 10FS. In conclusion, after long-term treatment, FS did not stimulate tumor growth and combined with TAM, regressed tumor size in part due to downregulation of the expression of estrogen-related gene products and signal transduction pathways.     

蛋白激酶C在乳腺癌组织中的表达

目的观察蛋白激酶C(protein kinase C,PKC)同工酶在乳腺癌组织中的表达状况,探讨癌细胞信息传递的分子生物学机制。方法应用半定量RT-PCR检测了31例乳腺癌组织与12例癌旁正常乳腺组织中PKC-βΙmR-NA表达;应用Western blot检测以上组织中PKC-βΙ蛋白表达。结果乳腺癌组织中PKC-βΙmRNA与蛋白表达均高于癌旁正常乳腺组织(P<0.001)。结论乳腺癌组织中存在PKC-βΙ同工酶过度表达,它可能介导乳腺癌细胞分化的信号转导过程。     

微小RNA-21在乳腺癌细胞中的作用

目的：探讨微小RNA（miR）-21在乳腺癌细胞（MCF7）中的作用。方法：对MCF7细胞转染miR-21,采用免疫组织化学法检测转染后程序性细胞凋亡4（PDCD4）表达;用噻唑蓝（MTT）比色法测转染miR-21后MCF7细胞增殖;流式细胞术检测转染后MCF7细胞凋亡。结果：经免疫组织化学检测,转染组未见染色,对照组细胞胞质呈棕褐色,转染组PDCD4的表达明显低于对照组,MTT法检测转染组细胞活力增加（P〈0.05）。转染组的凋亡率为（3.14±0.24）%,明显低于空白组、空质粒组的（8.04±0.02）%、（9.41±0.53）%,差异均有统计学意义（P〈0.05）。结论：PDCD4是miR-21的靶基因之一,miR-21的高表达可促进乳腺癌的发展。     

Flaxseed Lignans Enhance the Cytotoxicity of Chemotherapeutic Agents against Breast Cancer Cell Lines MDA-MB-231 and SKBR3

Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231. The experimental data suggests that flaxseed lignans significantly enhanced the ability of chemotherapeutic agents to cause cytotoxicity in SKBR3 and MDA-MB-231 breast cancer cells. A three compound combination study found that enterolactone and metformin together in combination with relatively low concentrations of chemotherapeutic drugs were able to significantly decrease cancer cell viability, compared to low concentrations of the individual chemotherapeutic drug alone. Our in vitro evaluation suggests a future direction in improving chemotherapeutic efficacy in breast cancer by adjuvant therapy with the flaxseed lignans.     

Approaches to Breast Cancer:

This article reviews surgical and chemotherapy treatment modalilies for breast cancer, from radical mastectomy to lumpectomy, including current knowledge of survival rates and the rationales behind cach procedure. Factors impeding clinical trials to determine the relative efficacies of each treatment are also discussed.     

Citrus Limonin Lacks the Antichemotherapeutic Effect in Human Models of Breast Cancer

Background/Aims: Chemicals that interfere with reactive oxygen species metabolism can act as potential candidates for the treatment of cancer. Some of the glucosides of citrus limonin inhibit the endogenously generated reactive oxygen species. The aim is to study the interactions of limonin with chemotherapy. Methods: Breast cancer cell lines MCF-7 (p53 wild type) and MDA-MB-231 (p53 mutant) as well as the nontumorigenic epithelial cell line MCF-10 were used to screen the effect of limonin at 1-, 5- and 10-μM concentrations with camptothecin for apoptosis and NF?B, p38 and ERK-MAPK signaling kinase assays. The effect of cyclophosphamide and limonin on MDA MB 231 xenografts was also studied. Results: Our results indicate that limonin did not inhibit camptothecin-induced apoptosis in human breast cancer cells in vitro through noninterference of camptothecin-induced phosphorylation of p38 MAPK and ERK-MAPK. Using an in vivo model of human breast cancer, limonin in combination with cyclophosphamide was not found to inhibit the cyclophosphamide-induced tumor regression through a reduced mitotic index of tumor xenograft cells when compared to treatment with cyclophosphamide alone. Conclusion: Both in vitro and in vivo results suggest that limonin could be beneficial for breast cancer patients undergoing chemotherapy.     

Antitumor Action of Amygdalin on Human Breast Cancer Cells by Selective Sensitization to Oxidative Stress

The treatment of MCF-7 and T47D human breast cancer cell lines with amygdalin was able to reduce the growth of both cells, in concentration and time-dependent manners. The potency of this inhibition against MCF-7 and T47D cells produced IC₅₀ values of 39 and 45?mM, respectively. To investigate the correlation of this inhibition with oxidative stress, an amygdalin treatment of both cell lines was capable of inducing the generation of malondialdehyde (MDA) and oxidized glutathione levels. Also, this treatment caused the decrease of total glutathione and glutathione reductase activity. The proportional survival of tumor cells from this inhibition was positively correlated with the total glutathione, but it was inversely correlated with amygdalin or MDA levels (P?<?0.001). In MCF-7 cells, the production of total glutathione was six times higher in the untreated than in amygdalin-treated cells, whereas this difference was reduced to 2.1 times in the T47D cells. Similarly, the production of MDA in MCF-7 cells was 2.4 times higher in the amygdalin-treated than in the untreated cultures, which were lowered to 1.3 times in the T47D cells. These data support a mechanism of amygdalin antitumor action against breast cancer cells based on the induction of oxidative stress.