Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex steroids control the proliferation of their target cells through two different pathways: 1) proliferative response (Step-1); and 2) inhibition of cell proliferation (Step-2). Mechanisms of cell proliferation regulation are incompletely understood; however, there is general agreement with the notion that sex steroid receptors play an important role in the control of the proliferation of sex steroid target cells. To test this hypothesis, a full human androgen receptor (AR) vector was transfected into human breast cancer MCF7 cells. The cloned cells that stably express the AR, called MCF7-AR1 cells, contained approximately five times more AR than the wild-type MCF7 cells from which they were derived. These AR-transfected cells retained their capacity to proliferate when estrogens were added to 10% charcoal-dextran stripped human serum but did not acquire the ability to proliferate when androgens were added to this medium. In serumless medium (ITDME), these cells proliferated maximally, as MCF7 cells did; however, natural and synthetic androgens prevented the AR-transfected cells from proliferating. Inhibition of cell proliferation occurred when physiological androgen concentrations (1 nM) were added to ITDME; this effect was almost completely reversed by Casodex, a synthetic androgen antagonist. Under the effect of androgens added to ITDME, MCF7-AR1 cells were arrested in the G0/G1 phase within 24 h. These data suggest that: 1) the androgen-induced inhibition of cell proliferation (Step-2) is AR-mediated; and 2) the AR may be necessary, but not sufficient, to mediate the androgen-induced proliferative response (Step-1).
 ...
PMID:Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptor. 907 95

This article summarizes discussions of the importance of androgens and androgen antagonists in the genesis of prostate cancer. These discussions occurred at a recent symposium on prostate cancer chemoprevention sponsored by the National Cancer Institute. Considerable information exists indicating the importance of androgens in the development of prostate cancer. Trials in breast cancer indicate that estrogen antagonists prevent breast cancer-suggesting, by analogy, that the blockade of androgen action might prevent the emergence of prostate cancer. The 5alpha-reductase inhibitors block the intracellular metabolism of testosterone and inhibit the growth of the prostate. Limited data suggest that 5alpha-reductase inhibitors reduces prostate-specific antigen in men with localized and advanced, primary or recurrent prostate cancer. An ongoing national trial of 18,000 men over 50 years of age has completed accrual and will evaluate whether a standard dose of finasteride will prevent the development of prostate cancer. The toxicity profile of finasteride (Proscar, Merck & Co., West Point, PA), the only approved 5alpha-reductase inhibitor, is favorable leading to its evaluation as a potential chemopreventive agent for prostate cancer. Anti-androgens such as bicalutamide (Casodex, AstraZeneca, Wilmington, DE) are active in the treatment of prostate cancer and comparable, in some trials, to testicular androgen suppression. These data suggest that antiandrogens may be active in the prevention of prostate cancer; however, the toxicity of antiandrogens (gynecomastia, gastrointestinal toxicity) poses concerns for application in prevention studies. Opportunities for study of factors predictive or associated with the development of prostate cancer and new agents that may interrupt this process offer numerous leads that may reduce the incidence of prostate cancer.
 ...
PMID:Androgen antagonists: Potential role in prostate cancer prevention. 1129 97

Members of Shc family conventionally serve as critical adaptors in tyrosine phosphorylation signal transduction pathways. p66(Shc) protein, a member of Shc family, is predominantly expressed in epithelial cells, whereas the regulation of its expression remains an enigma. We describe the effect of steroid hormones on the protein level of p66(Shc) and growth stimulation in hormone-sensitive human prostate, testicular and breast cancer cells. In DHT-treated androgen-sensitive prostate cancer LNCaP C-33 cells, the protein level of p66(Shc) was elevated by approximately 3-fold, correlating with increased cell growth. This DHT effect on p66(Shc) protein level and growth regulation was also observed in another androgen-sensitive prostate cancer cell line MDA PCa2b as well as 2 testicular cancer cell lines, Tera-1 and Tera-2 cells. Similarly, the female sex hormone estrogen had a stimulating effect on p66(Shc) protein level and proliferation in estrogen-sensitive MCF-7 breast cancer cells. The upregulation of p66(Shc) protein level by DHT was competitively abolished by Casodex, an androgen antagonist used to treat prostate cancer. Moreover, immunohistochemical analyses showed that the p66(Shc) protein level was significantly higher in primary prostate tumors than in adjacent non-cancerous cells (p < 0.05). The data collectively indicate that p66(Shc) protein levels correlate with steroid hormone-stimulated cell growth and prostate carcinogenesis.
 ...
PMID:p66Shc protein is upregulated by steroid hormones in hormone-sensitive cancer cells and in primary prostate carcinomas. 1469 93

Many men who undergo radical prostatectomy or radiotherapy for early prostate cancer have an excellent outcome; however, a significant proportion subsequently experience disease recurrence and/or cancer-related death. Adjuvant hormonal therapy after treatment of curative intent is given with the aim of eradicating undetected cancer cells outside the surgical margins or radiation field and/or micrometastatic disease. In the analogous setting of early breast cancer, adjuvant hormonal therapy is already established as standard care. Efficacy and tolerability data from the ongoing bicalutamide ('Casodex') Early Prostate Cancer program are expected to determine the role of adjuvant hormonal therapy with antiandrogens in early prostate cancer.
 ...
PMID:Success and failure of single-modality treatment for early prostate cancer. 1698 56

Epidermal growth factor (EGF) stimulates DNA synthesis and cytoskeletal rearrangement in human breast cancer (MCF-7) and human prostate cancer (LNCaP) cells. Both effects are inhibited by estrogen (ICI 182,780) and androgen (Casodex) antagonists. This supports the view that crosstalk exists between EGF and estradiol (ER) and androgen (AR) receptors and suggests that these receptors are directly involved in the EGF action. Our recent work shows that EGF stimulates ER phosphorylation on tyrosine and promotes the association of a complex between EGFR, AR/ER, and the kinase Src. The complex assembly triggers Src activity, epidermal growth factor receptor (EGFR) phosphorylation on tyrosine, and the EGF-dependent signaling pathway activation. In these cells, the AR/ER/Src complex is required for the EGF action, as the growth factor effects are abolished upon receptor silencing by specific SiRNAs and steroid antagonists or Src inhibition by the kinase inhibitor PP2.
 ...
PMID:Crosstalk between EGFR and extranuclear steroid receptors. 1726 67

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR and reduced estrogen receptor (ER) alpha mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERalpha-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERalpha that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen's agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers.
Breast Cancer Res Treat 2010 May
PMID:Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. 1953 38