Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.
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PMID:Clinical breast cancer, new developments in selection and endocrine treatment of patients. 144 97

We have introduced the human estrogen receptor (ER) gene into HeLa cells, a human adenocarcinoma cell line of uterine origin, by infection. The ER cDNA was inserted into a retroviral vector (pMV7-ER) which also contains the neomycin resistance gene to allow for selection of stable infected clones. Northern analysis showed exogenous ER expression in stable clones. The ER protein expressed was about 66 kDa, similar to native MCF-7 ER, and binds with high affinity to estrogen (E2). We have also observed that addition of E2 at 10(-8) M inhibits the growth of the I-1 clone which expresses high levels of the ER (223 fmol/mg cytosol protein). The inhibitory effects of E2 directly correlate with the quantity of ER in the cells. E2-induced gene expression analysis showed that pS2 and progesterone receptor (PgR), genes induced in MCF-7 cells by E2, are not induced in the ER+ HeLa clones. However, c-myc expression was found to be decreased and may be responsible for the observed growth inhibition by E2.
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PMID:Stable expression of the human estrogen receptor in HeLa cells by infection: effect of estrogen on cell proliferation and c-myc expression. 168 89

In search of critical genes in the mechanism of estrogen action in human breast cancer, we previously showed that estrogen stimulates transcription of the c-myc gene in estrogen-dependent (MCF-7) cells. We have now examined the role of c-myc in estrogen-stimulated growth of MCF-7 cells through the use of a synthetic antisense c-myc phosphorothioate oligonucleotide to specifically inhibit expression of the c-myc protein. Estrogen induces a 5-fold increase in c-myc protein expression within 90 min in steroid-deprived cells, as detected by Western blot. Prior exposure of MCF-7 cells to 10 microM c-myc antisense oligonucleotide results in up to 95% inhibition of the c-myc protein expression induced by estrogen. Antisense-myc oligonucleotide inhibits estrogen-stimulated cell growth by up to 75% over 9 days and also exerts a cytostatic effect on the growth of estrogen-independent MDA-MB-231 cells which show relatively high, constitutive expression of c-myc. Sense-myc and antisense-pS2 oligonucleotides have no effect on c-myc protein level or growth in either cell line. These results demonstrate both the specific and durable effects of antisense phosphorothioate oligonucleotides. Furthermore, these results indicate a critical role for c-myc in the growth of breast cancer cells and support the hypothesis that loss of estrogen regulation of this gene may be an important factor in the progression of breast cancer.
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PMID:Inhibition of c-myc expression by phosphorothioate antisense oligonucleotide identifies a critical role for c-myc in the growth of human breast cancer. 185 15

Previous articles have reported that the c-myb proto-oncogene was activated in various types of tumours of the hematopoietic system suggesting that this gene plays a role in the development of these malignancies. However no studies of the c-myb gene have as yet been performed in solid primary tumours. In the present study we have analysed in breast cancer the c-myb gene with the aim to determine its involvement in tumour progression. Expression of the c-myb oncogene was analysed from 169 carcinoma specimens obtained from untreated patients with non-inflammatory breast cancer (NBC) (112 patients) and inflammatory breast cancer (IBC) (57 patients). A 3.5 kb c-myb transcript band was detected in 108 (64%) tumours. c-myb expression was found to be associated with good prognostic factors (lowest histopathologic grade (P = 0.01), oestrogen and progesterone receptor status (P less than 10(-4)) and pS2 gene expression (P less than 10(-4)) and negatively correlated with breast cancers of poorer prognosis, namely IBC (P = 0.03) and NBC with multiple involved nodes (P = 0.15). Other genes (c-myc, c-erbB2, c-fos and epidermal growth factor receptor) were also studied. The c-myb gene expression was found to be inversely correlated (P less than 0.03) with only c-erbB2 overexpression in NBC. When data were analysed with a logistic regression model using a stepwise procedure, c-myb expression was found to be associated only with the oestrogen receptor status (P less than 10(-4)). In conclusion, our data indicate that analysis of c-myb expression in breast cancer could allow the characterization of a new class of oestrogen-dependent tumours.
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PMID:Strong association between c-myb and oestrogen-receptor expression in human breast cancer. 218 74

Xenograft tumours from an oestrogen-dependent human breast cancer cell line MCF-7 have been established and characterised in thymectomised, irradiated female CBA strain mice. There was evidence for selection in xenografts of a subpopulation of MCF-7 cells with an altered pattern of gene expression as measured by mRNA levels compared with the original cells in vitro. Tumorigenicity increased significantly on repeated animal passage but oestrogen dependence was retained. Following injection of the mice with oestrogen, mitosis was induced in the tumour cells with associated increases in thymidine uptake and percentage of cells in S-phase. In accord with these changes, c-myc and p53 expression were increased and TGF-beta was suppressed. Thereafter the expression of the c-myc and p53 genes fell whilst that of the TGF-beta gene was induced as the oestrogenic-stimulus declined. The oestrogen-regulated mRNA pS2 showed a biphasic response to oestrogen and levels declined as the serum oestrogen fell to undetectable levels. This xenograft system demonstrates that changes in transcription of oncogenes, growth factor and oestrogen-regulated genes can be detected in vivo in response to oestrogen. It thus provides an in vivo model for studies of the biochemical and molecular basis for therapeutic manipulation of hormone-sensitive human breast cancer.
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PMID:Gene expression in oestrogen-dependent human breast cancer xenograft tumours. 239 Apr 87

The expression of genes which may be involved in the regulation of human mammary epithelial cell growth [transforming growth factors alpha and beta] and tumorigenesis [c-myc, erbB2, epidermal growth factor receptor (EGFR), Ha-ras, pS2] has been compared in similarly cultured normal cell strains and tumor cell lines. We have found that the normal breast cells produce high levels of EGFR mRNA, which are translated into nearly 10(5) low affinity epidermal growth factor-binding molecules/cell. In the estrogen receptor-negative lines examined, the EGFR gene was expressed at levels comparable to those in the normal cells. In contrast, EGFR and transforming growth factor alpha mRNAs were reduced in estrogen receptor-positive tumor lines compared to estrogen receptor-negative lines and normal cells. Steady state mRNA levels for transforming growth factor beta, erbB2, c-myc, and Ha-ras in the normal cells were greater than or comparable to those in all of the breast tumor lines. Furthermore, in the absence of gene amplification, only one of the genes examined (i.e., pS2) was overexpressed in a subset of the tumor cells compared to their normal counterparts. Several reports by other investigators have described overexpression of some of these genes in breast biopsies and in tumor lines in studies lacking normal controls. Thus, our results, in which the same genes were not overexpressed compared to normal cells unless amplified, underscore the importance of including appropriate normal controls in studies aimed at defining aberrant patterns of gene expression in tumor cells.
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PMID:Expression of growth factors and oncogenes in normal and tumor-derived human mammary epithelial cells. 319 80

The growth-inhibitory actions of the pineal hormone, melatonin, on human breast tumor cells and the possible association between this inhibition and melatonin's down-regulation of the estrogen receptor (ER) expression were examined in the ER-positive, estrogen-responsive MCF-7 human breast tumor cell line. As previously reported, melatonin dramatically inhibits the growth of these breast tumor cells and down-regulates ER levels in these cells, suggesting that the modulation of ER may be an important mechanism by which melatonin inhibits breast cancer cell growth. In the present studies, Northern blot analysis was used to examine the expression of estrogen-regulated transcripts known to be involved in estrogen's mitogenic actions. Melatonin, at a physiologic concentration (10(-9) M), rapidly, significantly, and, in some cases, transiently elevated the steady-state mRNA levels of growth stimulatory products such as TGF alpha, c-myc, and pS2, which are normally up-regulated in response to estrogen. Conversely, melatonin decreased the expression of other factors normally up-regulated by estrogen, such as progesterone receptor and c-fos. Significant stimulation of the expression of the growth-inhibitory factor TGF beta was seen with melatonin treatment, potentially supporting the concept that melatonin's growth-inhibitory activity is mediated through the breast tumor cells' estrogen-response pathway. The early regulation of many of these products by melatonin suggests that mechanisms more rapid than the down-regulation of ER are important in melatonin's modulation of their expression. However, the long-term modulation of these transcripts (12-48 hr) may be heavily influenced by melatonin's down-regulation of ER expression. These results clearly define the need for additional in depth studies to dissect the cellular events leading to melatonin-induced growth inhibition in breast tumor cells.
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PMID:Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. 762 97

Amplification of c-myc and c-erb beta-2 (HER-2/neu) proto-oncogenes were analyzed in breast cancer tissues obtained from 100 patients without lymph node involvement (N-). An amplification of the c-myc gene was detected in four cases and a c-erb beta-2 (HER-2/neu) amplification in eight cases. The frequency of these abnormalities were compared to classical prognostic parameters as well as to new biological prognostic markers (cellular cycle, cathepsin-D and pS2 protein). Most of altered tumors were associated to some classical poor prognostic factors such as: steroid receptor-negative tumors, poorly differentiated tumors, high histoprognostic grade and tumor cell density. In contrast, no relation was found with new biological parameters. The analyses of these data in relation to clinical evolution will be of interest to evaluate their prognostic value.
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PMID:[Amplification of c-myc and c-erbbeta-2(HER-2/neu) in breast cancer without axillary lymph node metastasis: correlation with other prognostic parameters]. 770 67

Breast cancer is a complex but increasingly well-understood disease. Clearly, multiple alterations from normal mammary cells are required to achieve a transformed phenotype. Furthermore, there may be several possible alterations within broad categories that will produce the transformations leading to the malignant state. The specific set of alterations within a given cancer may thus provide necessary information about how it is unique and how it may best be treated. Several of the newer biologic markers of breast cancer may provide very specific treatment information. erbB-2 may predict for improved response to doxorubicin, rather than CMF. hsp 27 may predict for failure of doxorubicin. pS2 or EGFR may provide supplemental information predicting response to hormonal therapy. Each of these variables has strong evidence to support its use in this manner, but that evidence has been obtained on limited numbers of patients treated in a limited number of ways. The most established markers, with multiple studies indicating their prognostic benefit, are erbB-2, cathepsin D, and proliferation markers. Of the several proliferation markers there may be no one choice that is best. However, very clearly, any marker must be carefully assessed for appropriate cut-off values, and cut-off values established by one cohort of patients should be verified against another cohort of patients. The oncoproteins associated with cell cycle regulation (cyclin D, p53, Rb, and c-myc) have shown strong promise of providing important prognostic information. The limited studies to date indicate that these markers are independent of one another. Cell cycle regulation may be an area in which any defect may serve to deregulate the cell, and therefore several defects in one cell would be unlikely. The specific nature of the defect in a given cancer may be very important. With the advent of immunohistochemical methods to measure most of the markers, more information may become available. Finally, the burgeoning area of tumor-stromal interactions is replete with potentially important markers of cancer prognosis. The growth factors, which are marginally a part of this area owing to the probable importance of paracrine effects on cancer cell growth, have progressively developed a body of literature supporting their prognostic potential. However, they have rarely been studied in conjunction with the other aspects of tumor-stromal cooperation. The markers of metastatic potential, nm23 and angiogenesis, have been shown in small cohorts to have considerable prognostic import.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Overview of the biologic markers of breast cancer. 815 Jul 84

A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficulty accurately to predict the response to treatment. A valuable prognostic factor can be a poor predictive factor for response, and vice versa. High tumor levels of ER, PgR, AR and pS2 predict a relatively good response to endocrine therapy, while EGF-R positively, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high uPA levels indicate a high chance of poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, while MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low-risk patients, type of systemic treatment, and as targets for new treatment modalities.
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PMID:Cell biological factors associated with the response of breast cancer to systemic treatment. 848 34


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