Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone morphogenetic protein 7 (BMP-7) is an important regulator of cell development and differentiation of various organs. Tumorigenesis and tumor progression are also strongly associated with changes of the fate of cells which are highly differentiated in healthy tissues. Therefore, we studied the role of BMP-7 in breast cancer cell lines and in breast tumor tissue samples. BMP-7 is expressed in various cell lines, but in a cell line specific manner. The breast cancer cell lines MCF-7 and SK-BR-3 showed BMP-7 expression on the mRNA level. In T-47D we were not able to detect BMP-7 on the mRNA but on the protein level. Additionally, epidermal growth factor (EGF), a stimulator of proliferation, was not able to enhance BMP-7 expression on the transcriptional level. These findings are in contrast to the EGF-dependent regulation of BMP-6, indicating a differential regulation of these closely related TGF-beta members. In order to confirm the data obtained from cell cultures, we analyzed normal breast tissue and tumor tissue samples from 170 invasive ductal carcinomas of the breast by immunohistochemistry. We found BMP-7 expression in normal breast tissue in the end buds, but not in the ductus lactiferus. BMP-7 protein was detected in all 170 tumor samples. Comparing BMP-7 levels with histopathological parameters, we could not show a correlation of BMP-7 and the proliferation index nor with erbB receptors. But the expression of BMP-7 was highly correlated with estrogen receptor levels (p< or=0.01) and progesterone receptor levels (p< or =0.01) which are important markers for breast cancer prognosis and therapy.
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PMID:Differential expression and regulation of bone morphogenetic protein 7 in breast cancer. 1279 80

An increase in fibroblast growth factor-1 (FGF-1) is established as part of the cause of several important cancers including breast cancer, but the mechanisms by which it induces malignant behavior are not known. We now report that the protein 80K-H, a substrate for PKC, appears to be part of this mechanism and that it is increased in breast cancer and localizes to the nucleus as part of the mechanism. Our conclusion is based on an examination of a total of 58 biopsy specimens from human breast cancer patients for the presence of relationships between the 80K-H protein and the following: fibroblast growth factor receptor-1 (FGFR-1), tumor grade, microvessel counts (MVC), estrogen receptor (ER) and progesterone receptor (PgR) status. Based on histological grading and immunohistochemical (IHC) assays, we found strong direct relationships between 80K-H and FGFR-1 (r = 0.49, p = 0.003) and tumor grade (r = 0.42, p = 0.006). A trend for a direct relationship was observed with PgR (r=0.27, p=0.087). Notably, 80K-H immunostaining was largely limited to the epithelial cells of the mammary ducts. Subsequently, we studied the effects of FGF-1 on 80K-H in cultured human mammary carcinoma epithelial cells in order to establish a more direct relationship between these two molecules. We observed that FGF-1 treatment of MCF-7 cells stimulated translocation of 80K-H protein to the cell nucleus, as demonstrated by subcellular fractionation studies. Maximal intranuclear 80K-H was observed approximately 30 minutes following FGF-1 treatment. In addition, FGF-1 treatment of MCF-7 cells increased growth and invasion of MCF-7 cells, as demonstrated by cell proliferation and a modified Boyden chamber assay, respectively. Further support for 80K-H nuclearization was provided by the immunostaining of human breast cancer specimens and computer-assisted identification of a putative nuclear localization signal (NLS) near the amino terminus of 80K-H protein structure. These data support the existence of a previously unrecognized FGF-1/80K-H nuclear pathway in progression of human breast cancer and suggest that 80K-H may be useful for the assessment of breast tumor progression.
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PMID:Elevated 80K-H protein in breast cancer: a role for FGF-1 stimulation of 80K-H. 1284 77

Laminin is a basement membrane glycoprotein implicated in a large number of biologic activities of cancer progression, many of which are mediated by the presence of the laminin receptor (67LR) on the cell membrane. We studied the correlations of laminin and its receptor with standardized and new prognostic factors (including bone marrow micrometastases) in a series of 112 patients with operable breast cancers. Laminin-positive cells were detected in 60% of the tumors and 67LR-positive cells in 55%; both were present in 35% of the cases. No association was found between laminin or 67LR positivity and pathologic tumor size, pathologic nodal status, grading, Ki-67, estrogen receptor status, progesterone receptor status, or bone marrow micrometastases. The only statistically significant association was with menopausal status and age, with a higher percentage of 67LR-positive tumors among premenopausal and younger patients. The median follow-up was approximately 7 years. The prognosis of disease-free survival was similar in the laminin-positive and laminin-negative subjects but was significantly better in 67LR-negative patients; there were no significant differences in overall survival. The prognostic role of laminin and 67LR in disease-free survival and overall survival varied according to nodal status. In the absence of nodal involvement, the risk of relapse (and death) was greater in the patients who were positive for laminin, 67LR, or both than in those who were negative for laminin, 67LR, or both; in the case of 4 or more involved nodes, the prognostic role of laminin and 67LR was reversed. These results did not change after adjustment for age, menopausal status, tumor status, nodal status, grading, or bone marrow micrometastases.
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PMID:Prognostic significance of laminin, laminin receptor, and bone marrow micrometastases in breast cancer patients: are these markers of aggressive behavior and metastatic potential? 1466 56

Women exposed to exogenous progesterone have increased breast cancer risk, but the mechanisms of progesterone involvement in breast cancer development are unknown. In human breast and endometrium, progesterone receptor (PR) isoform expression is disrupted in premalignant lesions and predominance of one isoform, usually PRA, in invasive cancers is associated with poorer prognosis. Disrupted PR isoform expression results in disrupted progestin regulation of cell morphology, including rounded morphology and decreased adherence of cells to tissue culture flasks. The purpose of this study was to test the hypothesis that predominance of PRA affects the interaction of breast cancer cells with a physiologically relevant stromal tissue, bone marrow stroma. T-47D breast cancer cells demonstrated the ability to migrate into bone marrow fibroblasts and this was inhibited by progestin treatment. The antiprogestin RU38486 abrogated the progestin effect on migration, demonstrating that it was PR-mediated. In cells expressing a predominance of PRA, after induction of a stably integrated inducible PRA construct, the ability of progestin to inhibit breast cancer cell migration was lost. A number of integrins were progestin regulated in T-47D cells, but there was no difference in the progestin effect in cells with PRA predominance, nor were the levels of focal adhesion proteins altered in these cells. This suggested that the lack of inhibition by progestin of breast cancer cell migration in cells with PRA predominance was not mediated by PRA effects on the membrane components of the adherens junctions. In summary, this study has shown that PRA predominance has a striking functional effect on breast cancer cell migration into stromal layers. PRA predominance may render breast cancer cells relatively resistant to the inhibitory effects of progestins and one consequence of this may be increased invasion of stroma. If borne out in vivo, these findings suggest that tumours with PRA predominance may be predisposed to cancer progression and this may signal a poorer prognosis in patients.
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PMID:Effect of progesterone receptor a predominance on breast cancer cell migration into bone marrow fibroblasts. 1475 91

Knockout and expression studies suggest that estrogen receptor beta (ERbeta) plays a prominent role in ovarian function and pathology. Moreover, ovarian cancers are characterized by high morbidity and low responsiveness to anti-estrogens. Here we demonstrate, using quantitative PCR to measure ERalpha and ERbeta levels in 58 ovarian cancer patients, that ERbeta expression decreased in cysts and ovarian carcinomas as compared with normal ovaries and that this decrease is attributable only to a selective loss in ERbeta expression during cancer progression. To address the question of a possible involvement of ERbeta in ovarian cancers, we restored ERalpha and ERbeta expression in two human ovarian cancer cell lines PEO14 (ERalpha-negative) and BG1 (ERalpha-positive) using adenoviral delivery. ERalpha, but not ERbeta, could induce progesterone receptor and fibulin-1C. Moreover, ERalpha and ERbeta had opposite actions on cyclin D1 gene regulation, because ERbeta down-regulated cyclin D1 gene expression, whereas ERalpha increased cyclin D1 levels. Interestingly, ERbeta expression strongly inhibited PEO14 and BG1 cell proliferation and cell motility in a ligand-independent manner, whereas ERalpha had no marked effect. Induction of apoptosis by ERbeta also contributed to the decreased proliferation of ovarian cancer cells, as shown by Annexin V staining. This study shows that ERbeta is an important regulator of proliferation and motility of ovarian cancer and provides the first evidence for a proapoptotic role of ERbeta. The loss of ERbeta expression may thus be an important event leading to the development of ovarian cancer.
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PMID:Involvement of estrogen receptor beta in ovarian carcinogenesis. 1596 30

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.
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PMID:Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast. 1550 26

Apart from distinguishing the in vivo effects of progesterone (P) from those of estrogen (E), the progesterone receptor knockout (PRKO) mouse has furnished unprecedented access to novel cell-signaling paradigms, hitherto unsuspected. Along with providing new cellular principles by which P influences proliferative and differentiative programs obligate for tissue development and tumor progression, the PRKO in conjunction with transcript profiling has begun to uncover the transcriptional cascades underlying these processes. Moreover, studies on isoform-specific knockouts for PR-A (PR-AKO) and PR-B (PR-BKO) have clearly defined distinct physiological roles for the two subtypes of PR, providing essential physiological support for previous in vitro observations. Although the PR-AKO exhibits an infertility phenotype, the PR-BKO displays normal fecundity. Conversely, although normal mammary morphogenesis can manifest in the PR-AKO, pregnancy-associated mammary morphogenesis is severely impaired in the PR-BKO. By virtue of its ability to suppress E-induced and PR-B-mediated uterine and mammary proliferation, the PR-A isoform is likely to be an attractive drug target for the next generation of selective PR modulators in the treatment of uterine and mammary gland hyperplasia. Along with defining the dynamic interplay between E and P responses and physiological events mediated by PR-A and PR-B, further studies on these models should provide a broader conceptual framework for understanding abnormal progestin responses in vivo, with attendant implications for the management of female reproductive health and for the diagnosis and/or treatment of breast cancer.
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PMID:Revealing progesterone's role in uterine and mammary gland biology: insights from the mouse. 1571 87

Defects in mismatch repair (MMR) genes, particularly the hMSH2 and hMLH1 genes, are associated with a variety of cancers including sporadic breast cancer. However, whether or not patient clinical background, e.g. age, progesterone receptor (PR), estrogen receptor (ER), tumor progression and stage, chemotherapy history, and menopausal status, influences MMR status is not understood. To address these issues, 83 archival breast cancer specimens were examined for expression of hMSH2 and hMLH1 by immunohistochemistry and the relationship between MMR protein expression and patient clinical background was analyzed. We detected lack of or reduced expression of hMSH2 and hMLH1 in 23 (27.7%) and 26 cases (31.3%), respectively, and hypermethylation of the hMLH1 promoter accounted for the majority of the cases with reduced expression of hMLH1. Statistical analysis revealed that (i) reduced expression of hMLH1 and hMSH2 seemed to confer advantage for the progression of breast tumors to more advanced stages; (ii) attenuated expression of hMLH1 correlated with history of chemotherapy, but not with age, menopause, or the status of PR and ER; (iii) hypermethylation of the hMLH1 promoter was linked with clinical stage and lymphatic metastasis. These analyses indicate that defective expression of MMR genes is closely associated with the development of sporadic breast cancer.
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PMID:Roles of mismatch repair proteins hMSH2 and hMLH1 in the development of sporadic breast cancer. 1589 Feb 47

Changes in transcriptional regulation can be permissive for tumor progression by allowing for selective growth advantage of tumor cells. Tumor suppressors can effectively inhibit this process. The PMEPA1 gene, a potent inhibitor of prostate cancer cell growth is an androgen-regulated gene. We addressed the question of whether or not androgen receptor can directly bind to specific PMEPA1 promoter upstream sequences. To test this hypothesis we extended in silico prediction of androgen receptor binding sites by a modeling approach and verified the actual binding by in vivo chromatin immunoprecipitation assay. Promoter upstream sequences of highly androgen-inducible genes were examined from microarray data of prostate cancer cells for transcription factor binding sites (TFBSs). Results were analyzed to formulate a model for the description of specific androgen receptor binding site context in these sequences. In silico analysis and subsequent experimental verification of the selected sequences suggested that a model that combined a GREF and a GATA TFBS was sufficient for predicting a class of functional androgen receptor binding sites. The GREF matrix family represents androgen receptor, glucocorticoid receptor and progesterone receptor binding sites and the GATA matrix family represents GATA binding protein 1-6 binding sites. We assessed the regulatory sequences of the PMEPA1 gene by comparing our model-based GREF_GATA predictions to weight matrix-based predictions. Androgen receptor binding to predicted promoter upstream sequences of the PMEPA1 gene was confirmed by chromatin immunoprecipitation assay. Our results suggested that androgen receptor binding to cognate elements was consistent with the GREF_GATA model. In contrast, using only single GREF weight matrices resulted in additional matches, apparently false positives. Our findings indicate that complex models based on datasets selected by biological function can be superior predictors as they recognize TFBSs in their functional context.
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PMID:Androgen receptor binding sites identified by a GREF_GATA model. 1621 25

The recent discovery of the estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue offers new insights into the role of estrogens and their receptors in prostate cancer development and tumor progression. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the PR is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen Raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces the apoptotic cell death in a dose-dependent fashion. These data provide a rational for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.
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PMID:[Implications of estrogens and their receptors for the development and progression of prostate cancer]. 1622 Mar


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