Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its introduction more than 30 years ago, tamoxifen has been the most widely used endocrine therapy for the treatment of women with advanced breast cancer. More recently, a number of alternative endocrine treatments have been developed, including several selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and, most recently, fulvestrant ('Faslodex'). Fulvestrant is an estrogen receptor (ER) antagonist, which, unlike the SERMs, has no known agonist (estrogenic) effect and downregulates the ER protein. Tamoxifen is effective and well tolerated, although the non-steroidal AIs, anastrozole and letrozole, are more effective treatments for advanced disease than tamoxifen. Fulvestrant has recently gained US Food and Drug Administration approval for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. In two global phase III clinical trials fulvestrant was at least as effective and as equally well tolerated as anastrozole for the treatment of postmenopausal women with advanced and metastatic breast cancer. In a retrospective analysis of the combined data from these trials, mean duration of response was significantly greater for fulvestrant compared with anastrozole. These new hormonal treatments expand the choice of endocrine therapy for women with advanced breast cancer and offer new options for sequencing and combining treatments.
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PMID:Fulvestrant ('Faslodex')--a new treatment option for patients progressing on prior endocrine therapy. 1254 3

Fulvestrant (Faslodex) is a novel estrogen receptor (ER) antagonist that competitively binds to the ER with a much greater affinity than that of tamoxifen. The downregulation of cellular levels of the ER protein results in complete abrogation of estrogen-sensitive gene transcription. This distinct mechanism of action ensures a lack of cross resistance with other hormonal agents and, in contrast to tamoxifen, fulvestrant has no known estrogen-agonist effects. Fulvestrant is administered via monthly intramuscular injections (250mg) and is recommended for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The efficacy of fulvestrant was similar to that of the aromatase inhibitor anastrozole (1 mg/day) in two, well designed studies in postmenopausal women with locally advanced or metastatic breast cancer that had progressed during prior antiestrogen therapy. Time to disease progression (primary endpoint) and treatment failure, rates of objective response and clinical benefit, overall survival and quality of life were similar in patients treated with fulvestrant or anastrozole. In retrospective noninferiority analyses, fulvestrant was at least as effective as anastrozole in all randomised patients, and in those with or without visceral metastases. Fulvestrant is generally well tolerated and was tolerated as well as anastrozole in clinical trials. Treatment-related adverse events were mostly mild to moderate and led to treatment withdrawal in about 1% of patients who received fulvestrant or anastrozole. The main adverse effects associated with therapy are nausea, asthenia, pain, vasodilation and headache.In conclusion, monthly intramuscular injections of fulvestrant are at least as effective and as well tolerated as oral anastrozole once daily in the treatment of postmenopausal women with advanced breast cancer that has progressed on prior antiestrogen therapy. Because of a different mode of action to that of other hormonal agents, fulvestrant is effective in the treatment of tamoxifen-resistant disease and, unlike tamoxifen, has no known estrogen agonist effects. Thus, fulvestrant provides an effective and well tolerated option for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
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PMID:Fulvestrant: a review of its use in hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. 1501 96

Metastatic breast cancer cells are exposed to stress of detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. The purpose of this study was to explore a link between mammosphere growth, ECM gene expression, and the protein quality control system in the endoplasmic reticulum (ER). We compared the mRNA and protein levels of ER folding factors in SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres versus adherent conditions. Publicly available gene expression data for mammospheres formed by primary breast cancer cells and for circulating tumor cells (CTCs) were analyzed to assess the status of ECM/ER folding factor genes in clinically relevant samples. Knock-down of selected protein disulfide isomerase (PDI) family members was performed to examine their roles in SUM159PT mammosphere growth. We found that cells grown as mammospheres had elevated expression of ECM genes and ER folding quality control genes. CTC gene expression data for an index patient indicated that upregulation of ECM and ER folding factor genes occurred at the time of acquired therapy resistance and disease progression. Knock-down of PDI, ERp44, or ERp57, three members of the PDI family with elevated protein levels in mammospheres, in SUM159PT cells partially inhibited the mammosphere growth. Thus, breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER protein folding machinery. Targeting ER folding factors, in particular members of the PDI family, may improve the therapeutic outcomes in metastatic breast cancer.
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PMID:Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells. 2716 Dec 15

Our previous study demonstrated that high mRNA levels for Seven in Absentia Homolog 2 (SIAH2) correlated with high Estrogen Receptor (ER) mRNA levels and with longer progression-free survival (PFS) after first-line tamoxifen. Others showed high SIAH2 protein levels in ER-negative breast cancer associated with an unfavorable relapse-free survival. In the current study, we investigated SIAH2 protein expression to clarify the discrepancy between protein and mRNA findings and to determine its diagnostic value in breast cancer patients. Tissue microarrays (TMAs) containing core specimens of primary breast tumors were immunohistochemically stained for SIAH2 protein. The TMAs analyzed a cohort of 746 patients with primary breast cancer (PBC) and a cohort of 245 patients with ER-positive metastatic breast cancer (MBC) treated with first-line tamoxifen. SIAH2 staining was scored for intensity and proportion of positive tumor cells and evaluated for its relationship with metastasis-free survival (MFS) and PFS. Multivariate survival analyses included traditional prognostic or predictive factors, respectively. The PBC-cohort had 263 patients with high SIAH2 protein expression and decreased expression of ER protein and mRNA levels (P = 0.005 and P = 0.003, respectively). High SIAH2 levels correlated with significant unfavorable MFS in lymph node negative, ER-positive breast cancer patients. The MBC-cohort had 86 patients with increased SIAH2 protein expression. High SIAH2 expression was associated with an unfavorable PFS after first-line tamoxifen in multivariate analyses (HR = 1.45; 95% CI, 1.07-1.96; P = 0.015). In conclusion, SIAH2 protein expression is especially observed in ER-negative tumors. Its prognostic value in breast cancer does not add to current prognostic markers. The proportion of SIAH2-positive cells can be used as biomarker to predict tamoxifen treatment failure in MBC patients.
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PMID:SIAH2 protein expression in breast cancer is inversely related with ER status and outcome to tamoxifen therapy. 2718 2