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Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Because aromatase-dependent estrogen biosynthesis has been linked to hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 gene expression. The main objective of this study was to identify the receptors (EP) for prostaglandin E2 (PGE2) that mediate the induction of CYP19 transcription in human adipocytes and breast cancer cells. Treatment with PGE2 induced aromatase, an effect that was mimicked by either EP2 or EP4 agonists. Antagonists of EP2 or EP4 or small interference RNA-mediated down-regulation of these receptors suppressed PGE2-mediated induction of aromatase. PGE2 via EP2 and EP4 stimulated the cAMP->protein kinase A pathway resulting in enhanced interaction between P-CREB, p300, and the aromatase promoter I.3/II. Overexpressing a mutant form of p300 that lacks histone acetyltransferase activity suppressed PGE2-mediated induction of aromatase promoter activity. PGE2 via EP2 and EP4 also caused a reduction in both the amounts of BRCA1 and the interaction between BRCA1 and the aromatase promoter I.3/II. Activation of the aromatase promoter by PGE2 was suppressed by overexpressing wild-type BRCA1. Silencing of EP2 or EP4 also blocked PGE2-mediated induction of the progesterone receptor, a prototypic estrogen-response gene. In a mouse model, overexpressing COX-2 in the mammary gland, a known inducer of PGE2 synthesis, led to increased aromatase mRNA and activity and reduced amounts of BRCA1; these effects were reversed by knocking out EP2. Taken together, these results suggest that PGE2 via EP2 and EP4 activates the cAMP->PKA->CREB pathway leading to enhanced CYP19 transcription and increased aromatase activity. Reciprocal changes in the interaction between BRCA1, p300, and the aromatase promoter I.3/II contributed to the inductive effects of PGE2. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in women, affecting thousands of people each year. The majority of women are diagnosed with early stage breast cancer, which is curable. The follow-up care of the breast cancer survivor requires an understanding of the goals of follow-up and the short and long term side effects of breast cancer treatment. In this article, we will discuss the principles of follow-up care of the breast cancer survivor. [Copyright &y& Elsevier]

Cyclooxygenase-2 (COX-2) and Id-1 are overexpressed in avariety of human malignancies. Recently, each of these genes was found to play a role in mediating breast cancer metastasis to the lungs, but their potential interdependence was not evaluated. Hence, the main objective of the current study was to determine whether COX-2-derived prostaglandin (PGE2) activated Id-1 transcription, leading in turn to increased invasiveness of mammary epithelial cells. In MDA-MB-231 cells, treatment with PGE2 induced Id-1, an effect that was mimicked by an EP4 agonist. PGE2 via EP4 activated the epidermal growth factor receptor (EGFR) → ERK1/2 pathway, which led to increased expression of Egr-1. PGE2 stimulated EGFR signaling by inducing the release of amphiregulin, an EGFR ligand. The ability of PGE2 to activate Id-1 transcription was mediated by enhanced binding of Egr-1 to the Id-1 promoter. Silencing of COX-2 or pharmacological inhibition of COX-2 led to reduced PGE2 production, decreased Id-1 expression, and reduced migration of cells through extracellular matrix. A similar decrease in cell migration was found when Id-1 was silenced. The interrelationship between COX-2, PGE2, Id-1, and cell invasiveness was also compared in nontumorigenic SCp2 and tumorigenic SCg6 mammary epithelial cells. Consistent with the findings in MDA-MB-231 cells, COX-2-derived PGE2 induced Id-1, leading in turn to increased cell invasiveness. Taken together, these results suggest that PGE2 via EP4 activated the EGFR → ERK1/2 → Egr-1 pathway, leading to increased Id-1 transcription and cell invasion. These findings provide new insights into the relationship between COX-2 and Id-1 and their potential role in metastasis. [ABSTRACT FROM AUTHOR]

Summary: Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity. [Copyright &y& Elsevier]

Abstract: Objective: Previous studies demonstrate differing treatment patterns between older and younger patients with breast cancer. To explore the reasons for these disparities we conducted a survey of 28 oncologists specializing in breast cancer. Design and methods: Twenty-eight medical oncologists from Memorial Sloan-Kettering Cancer Center and the University of California Los Angeles who specialize in the treatment of breast cancer were asked to provide adjuvant treatment recommendations in hypothetical scenarios featuring older patients with high-risk breast cancer. For each of these hypothetical patients, the patient''s age was varied over four possible values (70, 75, 80, or 85 years of age) and health and functional status varied across three possible states (perfect health, average health, or major health problems). Survey data were compiled and analyzed to determine the impact of theoretical patient age, baseline health, and functional status on their treatment recommendations. Results: The proportion of oncologists who recommended adjuvant chemotherapy decreased as the patient''s age increased or as the patient''s functional status and health status decreased. For 96% of physicians (95% CI, 82–100%), patient age influenced chemotherapy recommendations, controlling for health/functional status; the same proportion of respondents were influenced by health/functional status, controlling for patient age. There was increased variability in treatment recommendations as the patient''s age increased or functional status and health status decreased. Conclusion: Among these medical oncologists who primarily treat breast cancer adjuvant treatment recommendations vary based on patient age, health, and functional status. Future studies are needed to correlate age, health, and functional status with the risks and benefits of adjuvant therapy so that consensus guidelines can be formed. A more comprehensive baseline assessment of the older patient, such as can be derived from a comprehensive geriatric assessment may be useful in this regard. [Copyright &y& Elsevier]

Purposes: To retrospectively determine the factors influencing treatment decisions in older breast cancer patients at a single center. Experimental design: 216 patients age &ges;75 seen in post-treatment follow-up between January, 1997 and June, 2000 were identified in the Memorial Sloan–Kettering breast cancer database. Eligible patients were &ges;75 years old at diagnosis, had a diagnosis of stage I, II, or III breast cancer, and received their follow-up care at Memorial Sloan Kettering Cancer Center. A retrospective chart review was performed. Patients were stratified by: (1) prognostic factors (age (75–79 or &ges;80), Charlson comorbidity score, tumor size, nodal status, stage, ER, PR, creatinine, albumin, hemoglobin, and liver function tests), (2) local treatment (lumpectomy, axillary lymph node dissection (AxLND), radiation (XRT), modified radical mastectomy (MRM)) and (3) systemic treatment (tamoxifen, chemotherapy). Combined local treatment was defined as (a) lumpectomy, AxLND, XRT or (b) MRM, AxLND, XRT (if tumor &ges;5 cm or &ges;4+ lymph nodes). Results: 96 patients were eligible for this study: 46 patients (75–79 years); 50 patients (&ges;80 years). The majority of patients (74%) were treated with lumpectomy but those &ges;80 were less likely to receive XRT (94% age 75–80; 45% age >80; P<0.01). Patients &ges;80 were also less likely to receive AxLND (94% age 75–79; 62% age &ges;80; P<0.01). A logistic regression model identified two independent prognostic variables for not receiving combined local treatment: increased age (P<0.01) and increased comorbidity score (P=0.01). Increased age did not correlate with increased comorbidity (P=0.48). 5.2% of patients received adjuvant chemotherapy (all age <80). 83% of ER positive patients received tamoxifen (89% age 75–79; 79% age >80). Conclusion: We hypothesize that both comorbidity and age play a significant role in influencing treatment decisions in the older breast cancer patient but these two variables are not necessarily correlated. Prospective studies are needed to determine the relative impact of these variables. [Copyright &y& Elsevier]

While ductal carcinoma in situ (DCIS) is known as a precursor lesion to most invasive breast carcinomas, the mechanisms underlying this transition remain enigmatic. DCIS is typically diagnosed by the mammographic detection of microcalcifications (MC). MCs consisting of non-stoichiometric hydroxyapatite (HA) mineral are frequently associated with malignant disease, yet it is unclear whether HA can actively promote malignancy. To investigate this outstanding question, we compared phenotypic outcomes of breast cancer cells cultured in control or HA-containing poly(lactide- co- glycolide) (PLG) scaffolds. Exposure to HA mineral in scaffolds increased the expression of pro-tumorigenic interleukin-8 (IL-8) among transformed but not benign cells. Notably, MCF10DCIS.com cells cultured in HA scaffolds adopted morphological changes associated with increased invasiveness and exhibited increased motility that were dependent on IL-8 signaling. Moreover, MCF10DCIS.com xenografts in HA scaffolds displayed evidence of enhanced malignant progression relative to xenografts in control scaffolds. These experimental findings were supported by a pathological analysis of clinical DCIS specimens, which correlated the presence of MCs with increased IL-8 staining and ductal proliferation. Collectively, our work suggests that HA mineral may stimulate malignancy in preinvasive DCIS cells and validate PLG scaffolds as useful tools to study cell-mineral interactions. [ABSTRACT FROM AUTHOR]