Breast Cancer Abstracts 14


Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients
            (Pierce et al., 2009)  Download
PURPOSE Chronic inflammation is believed to contribute to the development and progression of breast cancer. Systemic C-reactive protein (CRP) and serum amyloid A (SAA) are measures of low-grade chronic inflammation and potential predictors of cancer survival. PATIENTS AND METHODS We evaluated the relationship between circulating markers of inflammation and breast cancer survival using data from the Health, Eating, Activity, and Lifestyle (HEAL) Study (a multiethnic prospective cohort study of women diagnosed with stage 0 to IIIA breast cancer). Circulating concentrations of CRP and SAA were measured approximately 31 months after diagnosis and tested for associations with disease-free survival (approximately 4.1 years of follow-up) and overall survival (approximately 6.9 years of follow-up) in 734 disease-free breast cancer survivors. Cox proportional hazards models were used with adjustment for potential confounding factors to generate hazard ratios (HRs) and 95% CIs. Results Elevated SAA and CRP were associated with reduced overall survival, regardless of adjustment for age, tumor stage, race, and body mass index (SAA P trend < .0001; CRP P trend = .002). The HRs for SAA and CRP tertiles suggested a threshold effect on survival, rather than a dose-response relationship (highest v lowest tertile: SAA HR = 3.15; 95% CI, 1.73 to 5.65; CRP HR = 2.27; 95% CI, 1.27 to 4.08). Associations were similar and still significant after adjusting for self-reported history of cardiovascular events and censoring cardiovascular disease deaths. Elevated CRP and SAA were also associated with reduced disease-free survival, although these associations were of borderline significance (SAA P trend = .04; CRP P trend = .07). CONCLUSION Circulating SAA and CRP may be important prognostic markers for long-term survival in breast cancer patients, independent of race, tumor stage, and body mass index.

Inflammation and IGF-I activate the Akt pathway in breast cancer
            (Prueitt et al., 2007)  Download
Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p <or= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (p(interaction) < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E(2) induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival.

Oxidative stress, inflammation, and cancer: how are they linked?
            (Reuter et al., 2010)  Download
Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-kappaB, AP-1, p53, HIF-1alpha, PPAR-gamma, beta-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.


Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review).
            (Rose et al., 2002)  Download
Leptin is a hormone with multiple biological actions which is produced predominantly by adipose tissue; in humans, plasma levels correlate with total body fat, and particularly high concentrations occur in obese women. Several actions of leptin, including the stimulation of normal and tumor cell growth, migration and invasion, and enhancement of angiogenesis, suggest that this hormone can promote an aggressive breast cancer phenotype which can be estrogen-independent. This effect may involve activation of the transcription factor NFkappaB. Leptin can also induce aromatase activity, with the potential for the promotion of estrogen production from androstenedione in adipose tissue, and hence the stimulation of estrogen-dependent breast cancer progression. On this basis, we hypothesize that leptin, perhaps in association with insulin, the plasma concentrations of which correlate with those of leptin, has an important role in the known adverse effect of obesity on breast cancer.

Cancer screening in the United States, 2016: A review of current American Cancer Society guidelines and current issues in cancer screening.
            (Smith et al., 2016)  Download
Each year the American Cancer Society (ACS) publishes a summary of its guidelines for early cancer detection, data and trends in cancer screening rates, and select issues related to cancer screening. In this issue of the journal, we summarize current ACS cancer screening guidelines, including the update of the breast cancer screening guideline, discuss quality issues in colorectal cancer screening and new developments in lung cancer screening, and provide the latest data on utilization of cancer screening from the National Health Interview Survey.

8-Hydroxydeoxyguanosine: a new potential independent prognostic factor in breast cancer
            (Sova et al., 2010)  Download
BACKGROUND: 8-Hydroxydeoxyguanosine (8-oxodG) is the commonly used marker of oxidative stress-derived DNA damage. 8-OxodG formation is regulated by local antioxidant capacity and DNA repair enzyme activity. Earlier studies have reported contradictory data on the function of 8-oxodG as a prognostic factor in different cancer types. METHODS: We assessed pre-operative serum 8-oxodG levels with an enzyme-linked immunosorbent assay in a well-defined series of 173 breast cancer patients. 8-OxodG expression in the nuclei of cancer cells from 150 of these patients was examined by immunohistochemistry. RESULTS: The serum 8-oxodG levels and immunohistochemical 8-oxodG expression were in concordance with each other (P<0.05). Negative 8-oxodG immunostaining was an independent prognostic factor for poor breast cancer-specific survival according to the multivariate analysis (P<0.01). This observation was even more remarkable when ductal carcinomas only (n=140) were considered (P<0.001). A low serum 8-oxodG level was associated statistically significantly with lymphatic vessel invasion and a positive lymph node status. CONCLUSIONS: Low serum 8-oxodG levels and a low immunohistochemical 8-oxodG expression were associated with an aggressive breast cancer phenotype. In addition, negative 8-oxodG immunostaining was a powerful prognostic factor for breast cancer-specific death in breast carcinoma patients.

An essay on sexual frustration as the cause of breast cancer in women: how correlations and cultural blind spots conceal causal effects
            (Stuger, 2012)  Download
The main premise of this hypothesis is that breast cancer is caused by sexual frustration. Sexual frustration is triggered by multiple forms of dissonance between the absence or lack of sexual reward and the (un)conscious motivation to obtain these sexual rewards. I assume that neural and hormonal processes are capable of adjusting or distorting biologically active forms of specific sex hormones depending on experienced sexual stimuli. I hypothesize that prolonged sexual frustration will ultimately lead via aberrantly metabolized sex hormones to the development of breast cancer. Human female sexual behavior research links sexual frustration with breast cancer risk. The distinction between human female sexual behavior and reproduction is crucial to understand breast cancer risk. Current explanations are focused on reproduction. However, human female sexual behavior is causal in breast cancer development and androgens rather than estrogens are crucial for sexual behaviors in women. Social learning is the main determinant of human sexual behaviors that is why cultural and social processes are very important to understand breast cancer risk. Epidemiologists should evaluate breast cancer risk based on cultural female attitudes towards sexually related issues. Female mate choices should be examined for (un)conscious cultural, ethnic, religious, and socio-economic pressure to make a thorough assessment of breast cancer risk. Closer examination of (un)conscious female copulation strategies reveal that they are potential sources of sexual frustration in specific groups of women. Postmenopausal women seem vulnerable for self-fulfilling prophecies about post reproductive sexuality, body image, and negative perceptions of menopause which may cause sexual frustrations.

Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells.
            (Sundar et al., 2008)  Download
MCF7 cells are an estrogen-responsive human breast cancer cell line that expresses both estrogen receptor (ER) alpha and ERbeta. Treatment of MCF7 cells with artemisinin, an antimalarial phytochemical from the sweet wormwood plant, effectively blocked estrogen-stimulated cell cycle progression induced by either 17beta-estradiol (E(2)), an agonist for both ERs, or by propyl pyrazole triol (PPT), a selective ERalpha agonist. Artemisinin strongly downregulated ERalpha protein and transcripts without altering expression or activity of ERbeta. Transfection of MCF7 cells with ERalpha promoter-linked luciferase reporter plasmids revealed that the artemisinin downregulation of ERalpha promoter activity accounted for the loss of ERalpha expression. Artemisinin treatment ablated the estrogenic induction of endogenous progesterone receptor (PR) transcripts by either E(2) or PPT and inhibited the estrogenic stimulation of a luciferase reporter plasmid driven by consensus estrogen response elements (EREs). Chromatin immunoprecipitation assays revealed that artemisinin significantly downregulated the level of endogeneous ERalpha bound to the PR promoter, whereas the level of bound endogeneous ERbeta was not altered. Treatment of MCF7 cells with artemisinin and the pure antiestrogen fulvestrant resulted in a cooperative reduction of ERalpha protein levels and enhanced G(1) cell cycle arrest compared with the effects of either compound alone. Our results show that artemisinin switches proliferative human breast cancer cells from expressing a high ERalpha:ERbeta ratio to a condition in which ERbeta predominates, which parallels the physiological state linked to antiproliferative events in normal mammary epithelium.

Modulation of CYP1A1, CYP1A2 and CYP1B1 expression by cabbage juices and indoles in human breast cell lines.
            (Szaefer et al., 2012)  Download
Epidemiological studies have shown that consumption of cabbage and sauerkraut is connected with significant reduction of breast cancer incidences. Estrogens are considered a major breast cancer risk factor and their metabolism by P450 enzymes substantially contributes to carcinogenic activity. The aim of this study was to investigate the effect of cabbage and sauerkraut juices of different origin on the expression profile of the estrogen metabolism key enzymes (CYP1A1, CYP1A2, CYP1B1) in breast cell lines MCF7, MDA-MB-231, and MCF10A. The effects of cabbage juices were compared with that exerted by indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM). The treatment with cabbage juices or indoles for 72 h affected the expression of CYP1 family genes in cell-type dependent manner. Their induction was found in all cell lines, but the ratio of CYP1A1 to CYP1B1 was 1.22- to 10.6-fold in favor to CYP1A1 in MCF7 and MCF10A cells. Increased levels of CYP1A2 in comparison with CYP1B1 were also observed in MCF7 cells. In contrast, in MDA-MB-231 cells CYP1B1 was preferentially induced. Since the cell lines investigated differ in invasion capacity, these results support epidemiological observations and partly explain the mechanism of the chemopreventive activity of white cabbage products.


Dietary intakes of omega-6 and omega-3 polyunsaturated fatty acids and the risk of breast cancer.
            (Thiébaut et al., 2009)  Download
Experimental studies suggest detrimental effects of omega-6 polyunsaturated fatty acids (PUFA), and beneficial effects of omega-3 PUFAs on mammary carcinogenesis, possibly in interaction with antioxidants. However, PUFA food sources are diverse in human diets and few epidemiologic studies have examined whether associations between dietary PUFAs and breast cancer risk vary according to food sources or antioxidant intakes. The relationship between individual PUFA intakes estimated from diet history questionnaires and breast cancer risk was examined among 56,007 French women. During 8 years of follow-up, 1,650 women developed invasive breast cancer. Breast cancer risk was not related to any dietary PUFA overall; however, opposite associations were seen according to food sources, suggesting other potential effects than PUFA per se. Breast cancer risk was inversely associated with alpha-linolenic acid (ALA) intake from fruit and vegetables [highest vs. lowest quintile, hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63, 0.88; p trend < 0.0001], and from vegetable oils (HR 0.83; 95% CI 0.71, 0.97; p trend 0.017). Conversely, breast cancer risk was positively related to ALA intake from nut mixes (p trend 0.004) and processed foods (p trend 0.068), as was total ALA intake among women in the highest quintile of dietary vitamin E (p trend 0.036). A significant interaction was also found between omega-6 and long-chain omega-3 PUFAs, with breast cancer risk inversely related to long-chain omega-3 PUFAs in women belonging to the highest quintile of omega-6 PUFAs (p interaction 0.042). These results emphasize the need to consider food sources, as well as interactions between fatty acids and with antioxidants, when evaluating associations between PUFA intakes and breast cancer risk.

Igf-I influence on breast cancer cell survival
            (Van Den Berg, 2003)  Download
The insulin-like growth factor system has been implicated in the proliferative control of breast cancer cells. In addition to this function, IGF action can also protect cells from programmed cell death. Substantial knowledge has been gained about death effector molecules and their regulation in breast cancer. IGF receptor can influence several key cell death pathways. In this review, we will focus on the intracellular mechanisms activated by IGF-I that influence cell survival.


The Ras-association domain family (RASSF) members and their role in human tumourigenesis.
            (van der Weyden and Adams, 2007)  Download
Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in approximately 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1-8). RASSF1-6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7-8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours.

Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study.
            (Yao et al., 2011)  Download
BACKGROUND:  Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive. It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity. METHODS AND FINDINGS:  In case-control and case-series analyses, we examined serum concentrations of 25-hydroxyvitamin D (25OHD) in relation to breast cancer prognostic characteristics, including histologic grade, estrogen receptor (ER), and molecular subtypes defined by ER, progesterone receptor (PR) and HER2, among 579 women with incident breast cancer and 574 controls matched on age and time of blood draw enrolled in the Roswell Park Cancer Institute from 2003 to 2008. We found that breast cancer cases had significantly lower 25OHD concentrations than controls (adjusted mean, 22.8 versus 26.2 ng/mL, p<0.001). Among premenopausal women, 25OHD concentrations were lower in those with high- versus low-grade tumors, and ER negative versus ER positive tumors (p≤0.03). Levels were lowest among women with triple-negative cancer (17.5 ng/mL), significantly different from those with luminal A cancer (24.5 ng/mL, p = 0.002). In case-control analyses, premenopausal women with 25OHD concentrations above the median had significantly lower odds of having triple-negative cancer (OR = 0.21, 95% CI = 0.08-0.53) than those with levels below the median; and every 10 ng/mL increase in serum 25OHD concentrations was associated with a 64% lower odds of having triple-negative cancer (OR = 0.36, 95% CI = 0.22-0.56). The differential associations by tumor subtypes among premenopausal women were confirmed in case-series analyses. CONCLUSION:  In our analyses, higher serum levels of 25OHD were associated with reduced risk of breast cancer, with associations strongest for high grade, ER negative or triple negative cancers in premenopausal women. With further confirmation in large prospective studies, these findings could warrant vitamin D supplementation for reducing breast cancer risk, particularly those with poor prognostic characteristics among premenopausal women.

Meta-analysis: serum vitamin D and breast cancer risk.
            (Yin et al., 2010)  Download
We reviewed and summarised observational epidemiological studies regarding the association between serum vitamin D (measured as 25(OH)D levels) and the risk of breast cancer (BC). Relevant studies published until September 2009 were identified by systematically electronic searching Ovid Medline, EMBASE and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardised manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, BC incidence/BC mortality according to serum 25-hydroxyvitamin D (25(OH)D) and the respective ratios, and covariates adjusted for in the analysis. All existing observational epidemiological studies that reported at least one serum 25(OH)D level in subjects in any time period before or after a diagnosis of breast cancer were included in our review. Individual and summary risk ratios (RRs) for an increase of serum 25(OH)D by 20ng/ml were calculated using meta-analysis methods. Only 25(OH)D was considered. Overall, 10 articles were included. Specific results for BC incidence were reported in nine articles and for BC mortality in one article. In meta-analyses, summary RRs (95% confidence interval (CI)) for an increase of 25(OH)D by 20ng/ml were 0.59 (0.48-0.73), 0.92 (0.82-1.04) and 0.73 (0.60-0.88) with P values of <0.001, 0.164 and 0.001 for case-control studies, nested case-control studies and both study designs combined, respectively. No indication for publication bias was found, but there was large heterogeneity between studies. In conclusion, while case-control studies with measurement of 25(OH)D after diagnosis suggest an inverse association, a statistically significant inverse association remained unconfirmed in prospective studies with measurement of 25(OH)D years before diagnosis. Further studies are needed to clarify the potential role and the relevant exposure time regarding vitamin D and breast cancer risk.



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