Elizabeth A. Peralta

Reactive astrocytes promote the metastatic growth of breast cancer stem-like cells by activating Notch signalling in brain

Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL‐1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem‐like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up‐regulated HES5 followed by promoting self‐renewal of CSCs. Furthermore, we have shown that the blood‐brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re‐establish their niche for their self‐renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

American Ginseng Inhibits Induced COX-2 and NFKB Activation in Breast Cancer Cells

BACKGROUND Epidemiologic evidence suggests reduced breast cancer mortality in users of American Ginseng (AG) (Panax quinquefolium). We hypothesized that AG extract decreases proliferation of human breast cancer cells via an anti-inflammatory effect applicable to the prevention of breast and other cancers. MATERIAL AND METHODS A defined lyophilized aqueous extract of AG (LEAG) was dissolved in DMSO 1mg/mL, and serially diluted in saline. The cell lines MDA MB 231 and MCF7 were stimulated with the phorbol ester PDBu and treated with 100-500 mcg/mL LEAG. Proliferation was measured by MDA assay. Induced COX-2 expression was assayed by ELISA. Activation of NFkappaB by phosphorylation of the p65 subunit was quantified by CASE (cellular activation of signaling ELISA). RESULTS Both cell lines had reduced proliferation when treated with LEAG. PDBu stimulation of MDA MB 231 increased expression of the COX-2 protein 20-fold at 48 hours (P<0.005). COX-2 protein expression remained at baseline concentrations in PDBu- treated MDA MB 231 cells exposed to 100 mcg/mL LEAG. The CASE assay showed a 4-fold increase in p65 activation 24 hours after PDBu treatment in normal medium, while phosphorylated p65 dropped below baseline in the cells treated with PDBu plus LEAG. CONCLUSION In MDA MB 231, COX-2 was inducible with PDBu. This induced COX-2 expression was blocked by 100 microgram/mL LEAG in a time course consistent with the decline in the activated p65 subunit of NFkappaB. These results provide an anti-inflammatory mechanism for a possible anti-cancer effect of American Ginseng.

Biology of the estrogen receptor, GPR30, in triple negative breast cancer.

BACKGROUND Triple-negative (TN) breast cancer lacks a known signaling pathway amenable to targeted therapy. The authors hypothesized that the G protein-coupled receptor GPR30 may be present in TN breast cancer and serve a role for tumor growth. METHODS A retrospective pathology study and chart review were conducted. All patients aged ≤49 years from 2000 to 2008 were included (n = 24). Concurrent patients aged ≥50 years were randomly selected. Paraffin sections were stained for GPR30 and reviewed by a pathologist blinded to estrogen receptor and progesterone receptor status. Disease-free survival was analyzed versus age and receptor status. Means were compared using 2-sample t tests and proportions using chi-square analysis. RESULTS Twenty-seven patients tested GPR30 positive and 21 GPR30 negative. Seventeen of 18 TN cancers tested positive for GPR30 (P < .0001). Recurrence at a mean follow-up of 36 months was 22.2% in the GPR30-positive group and 9.5% in the GPR30-negative group. CONCLUSIONS GPR30 is prevalent in TN breast cancer and associated with young age and possibly recurrence.

Rare Anorectal Neoplasms: Gastrointestinal Stromal Tumor, Carcinoid, and Lymphoma

Several uncommon tumors occur in the anal canal such as gastrointestinal stromal tumors, carcinoids, and lymphoma. Increased clinical experience and advancements in molecular biology have improved the accuracy of pathologic diagnosis and guided treatment recommendations, which the author addresses in this article.

Vitamin E Increases Biomarkers of Estrogen Stimulation When Taken With Tamoxifen

BACKGROUND Vitamin E (alpha-tocopherol acetate, AT) diminishes the antiproliferative effect of tamoxifen on breast cancer cells in vitro. METHODS A prospective study of seven women taking tamoxifen for adjuvant therapy of breast cancer. Four who were already taking AT supplements had random core biopsies of the normal breast and again 30 days after discontinuing AT. Three who were not on AT had biopsies before and after adding AT 400 mg for 30 days. Biopsies were stained for estrogen receptor (ER) and the mitogen-activated protein kinase p-ERK. Tissue extracts were assayed for p-ERK by enzyme-linked immunosorbent assay. Serum levels of alpha-tocopherol and tamoxifen were measured. RESULTS Five out of seven patients had lower tamoxifen levels while taking AT, four of these went to subtherapeutic levels. Biopsies showed 23% of ductal cells were ER positive when patients were off AT and 70% on AT (P = 0.02). P-ERK staining was 21% off AT and 82% on AT. Five of seven patients had significantly higher tissue p-ERK when on AT. CONCLUSIONS Biomarkers of estrogen-stimulation (ER, progesterone receptor, and p-ERK) were higher in breast biopsies of women taking vitamin E supplements while taking tamoxifen. Findings suggest that vitamin E supplements may interfere with the therapeutic effects of tamoxifen.