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1.  Orbital Metastasis of Breast Carcinoma 
We report a case of orbital metastasis in a previously diagnosed metastatic breast cancer in a 46-year old woman presenting with diplopia and proptosis of her left eye bulb. An orbital computed-tomography (CT) and a magnetic resonance imaging (MRI) both revealed an intra-orbital extra-bulbar mass of 1.5 × 3 cm in size, in the left orbit. The patient had been diagnosed with stage IV breast cancer 4 years before. She had received chemotherapy with docetaxel and was on hormone therapy at the time of presentation of her eye symptoms. Current treatment included systemic combination therapy with docetaxel and capecitabine as well as local irradiation with stereotactic radiosurgery (cyberknife). There was a gradual improvement of local symptoms and signs. The metastatic involvement of the orbit in malignant tumors is a rarely diagnosed condition. Breast cancer accounts for the majority of these cases. The appearance of eye symptoms in patients with a history of cancer should always be investigated with a consideration of ocular metastatic disease.
PMCID: PMC3086305  PMID: 21556252
orbital metastases; breast cancer; orbit
2.  Characterization of a Test for Invasive Breast Cancer Using X-ray Diffraction of Hair—Results of a Clinical Trial 
Objective:
To assess the performance of a test for breast cancer utilizing synchrotron x-ray diffraction analysis of scalp hair from women undergoing diagnostic radiology assessment.
Design and Setting:
A double-blinded clinical trial of women who attended diagnostic radiology clinics in Australia.
Patients:
1796 women referred for diagnostic radiology, with no previous history of cancer.
Main Outcome Measures:
Sensitivity, specificity and accuracy of the hair test analysis compared to the gold standard of imaging followed by biopsy where indicated.
Results:
The hair-based assay had an overall accuracy of >77% and a negative predictive value of 99%. For all women, the sensitivity of both mammography and X-ray diffraction alone was 64%, but when used together the sensitivity rose to 86%. The sensitivity of the hair test for women under the age of 70 was 74%.
Conclusion:
In this large population trial the association between the presence of breast cancer and an altered hair fibre X-ray diffraction pattern previously reported has been confirmed. It appears that mammography and X-ray diffraction of hair detect different populations of breast cancers, and are synergistic when used together.
PMCID: PMC3086309  PMID: 21556251
X-ray diffraction; hair; breast cancer; randomized clinical trial; synchrotron
3.  VEGF 936C > T Polymorphism and Association of BI-RADS Score in Women with Suspected Breast Cancer 
Purpose:
Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumors. A 936C > T polymorphism in the VEGF gene has been associated with reduced VEGF plasma levels. Purpose of the present study was to analyze the potential association between VEGF genotype and radiological appearance of breast lesions by mammography.
Materials and Methods:
Fifty two women with 54 suspected breast lesions were analyzed by the use of mammography with the standard breast imaging reporting and data systems (BI-RADS). Germline VEGF genotype was determined in all subjects by allele-specific digestion of amplification products. An open biopsy was performed on all lesions.
Results:
VEGF CC, CT and TT genotypes were found in 41 (79%), 9 (17%) and 2 (4%) patients. By mammography 26, 16 and 12 suspected breast lesions were classified as BI-RADS scores 3, 4 and 5, respectively. Both carriers of the TT genotype were classified as BI-RADS 5, whereas among CT or CC carriers, BI-RADS scores 3, 4 and 5 were found in 26, 16 and 10 subjects (P < 0.026).
Conclusion:
The VEGF 936C > T polymorphism seems to be associated with a high BI-RADS score in women with suspicious breast lesions.
PMCID: PMC3086306  PMID: 21556250
vascular endothelial growth factor; VEGF; breast cancer; polymorphism
4.  Modulation of the BRCA1 protein and induction of apoptosis in triple negative breast cancer cell lines by the polyphenolic compound curcumin 
In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.
PMCID: PMC2756684  PMID: 19809577
mammary carcinoma; triple negative; curcumin; DNA damage; BRCA1
5.  Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin 
In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have limited non-specific toxicity. This study suggests that curcumin and potentially curcumin analogues should be tested further in the context of triple negative breast cancer. These results are novel, having never been previously reported, and suggest that curcumin could provide a novel, non-toxic therapy, which could lead to improved survival for patients with triple negative breast cancer. Curcumin should be studied further in this subset of breast cancer patients, for whom treatment options are severely limited.
PMCID: PMC2756684  PMID: 19809577
mammary carcinoma; triple negative; curcumin; DNA damage; BRCA1
6.  Growth Factor Receptors and Apoptosis Regulators: Signaling Pathways, Prognosis, Chemosensitivity and Treatment Outcomes of Breast Cancer 
Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens.
PMCID: PMC3086304  PMID: 21556249
prognostic markers; estrogen; growth factor receptor; apoptosis; chemotherapy; mitogen-activated protein kinase
7.  Quality of Life and Neutropenia in Patients with Early Stage Breast Cancer: A Randomized Pilot Study Comparing Additional Treatment with Mistletoe Extract to Chemotherapy Alone 
Background:
Chemotherapy for breast cancer often deteriorates quality of life, augments fatigue, and induces neutropenia. Mistletoe preparations are frequently used by cancer patients in Central Europe. Physicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy. Mistletoe preparations also have immunostimulant properties and might therefore have protective effects against chemotherapy-induced neutropenia.
Patients and Methods:
We conducted a prospective randomized open label pilot study with 95 patients randomized into three groups. Two groups received Iscador® M special (IMS) or a different mistletoe preparation, respectively, additionally to chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluoro-uracil (CAF). A control group received CAF with no additional therapy. Here we report the comparison IMS (n = 30) vs. control (n = 31). Quality of life including fatigue was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Neutropenia was defined as neutrophil counts <1,000/μl and assessed at baseline and one day before each CAF cycle.
Results:
In the descriptive analysis all 15 scores of the EORTC-QLQ-C30 showed better quality of life in the IMS group compared to the control group. In 12 scores the differences were significant (p < 0.02) and nine scores showed a clinically relevant and significant difference of at least 5 points. Neutropenia occurred in 3/30 IMS patients and in 8/31 control patients (p = 0.182).
Conclusions:
This pilot study showed an improvement of quality of life by treating breast cancer patients with IMS additionally to CAF. CAF-induced neutropenia showed a trend to lower frequency in the IMS group.
PMCID: PMC3086310  PMID: 21556248
mistletoe thereapy; breast cancer; randomized clinical trial; quality of life; neutropenia
8.  Effects of Celecoxib and Ly117018 Combination on Human Breast Cancer Cells in Vitro 
Activation and signalling of estrogen receptor (ER) and COX-2 represent two important pathways in breast cancer cell regulation. Activation of either pathway is associated with breast cancer cell proliferation and eventually malignant progression. Raloxifene analogue, Ly117018, a selective estrogen receptor modulator and celecoxib, a specific COX-2 inhibitor have been shown to inhibit breast cancer cell proliferation when used alone in vitro and in vivo. In this study, the combined drug effects on hormone-dependent MCF-7 and hormone-independent MDA-MB-435 cells in vitro were evaluated. Cell proliferation assays excluded drug antagonism and revealed a moderate synergistic growth inhibitory activity of Ly117018 and celecoxib on both cell lines when combined in specific concentrations. Growth inhibition of either compound was not associated with cell cycle arrest. In MCF-7 cells, western blot analysis revealed a decreased phosphorylation of the AKT protein by either agent alone or in combination. In MDA-MB-435 cells, celecoxib alone induced an increase in AKT phosphorylation relative to total AKT protein; this effect was decreased in the presence of Ly117018. These results indicate that these two drugs are non-antagonistic; and when combined in specific concentrations, moderate synergistic antiproliferative activity of celecoxib and Ly117018 were observed in hormone-dependent MCF-7 and hormone-independent MDA-MB-435 cells associated with changes in cell cycle distribution and regulation of AKT protein and phosphorylation. These findings further support a central role of the ER- and COX-2 pathways in human breast cancer cells.
PMCID: PMC3086307  PMID: 21556247
SERM; estrogen receptor; COX-2; celecoxib; Ly117018; drug synergism
9.  Expression of Estrogen Sulfotransferase 1E1 and Steroid Sulfatase in Breast Cancer: A Immunohistochemical Study 
It is known that the steroid sulfatase (STS) and the estrogen sulfotransferase (EST1E1) are commonly expressed in human breast carcinomas. STS and EST1E1 combined action could maintain the equilibrium between sulfated (inactive) and unconjugated (active) estrogens, which might have effects on development of hormone dependent breast cancer.
We studied the expression of the STS and EST1E1 in 88 breast carcinomas and 57 adjacent non-malignant tissues by immunohistochemistry. The results were correlated with the tumor expression of estrogen receptor α (ER-α) and β (ER-β), progesterone receptor A (PR-A) and B (PR-B) and the proliferation marker CDC47, the tumoral type and stage and the age at surgery.
STS expression was higher in carcinoma specimens than in adjacent normal tissues, although not to a significant level (p = 0.064) and it was positively associated with CDC47 expression (p < 0.05). These observations support the hypothesis that STS is overexpressed in breast cancer and associated with a worse prognosis.
EST1E1 was observed for the first time in the nuclei of epithelial and tumoral cells. Tumor expression of EST1E1 was positively correlated with ER-β (p < 0.01) and PR-B (p < 0.05), two steroid receptors already associated with an improve prognosis for breast cancer.
Controlling the STS overexpression in carcinomas could be a way to inhibit cancer growth. The significance of the association between EST1E1 and ER-β or PR-B should be further studied since these two receptors are transcription activators and may regulate the expression of protective enzymes like EST1E1.
PMCID: PMC3086308  PMID: 21556246
breast cancer; EST1E1; STS; immunohistochemistry
10.  Urine Biomarkers of Risk in the Molecular Etiology of Breast Cancer 
Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen-DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies.
PMCID: PMC3086311  PMID: 21556245
breast cancer risk; depurinating estrogen-DNA adducts; urinary estrogen biomarkers; balance in estrogen metabolism

Results 1-10 (10)