Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Potential mechanisms for tamoxifen resistance include loss or alteration in estrogen receptor or other transcription factors and altered tamoxifen pharmacology. Using an experimental model, we have previously demonstrated that one form of tamoxifen resistance is related to the acquired ability of tamoxifen to stimulate tumor growth. These tamoxifen-stimulated tumors contain a reduced tamoxifen concentration and an altered metabolite profile suggesting that accumulation of more estrogenic metabolites could explain this phenomenon. However, in vivo treatment of nude mice carrying tamoxifen-stimulated tumors with fixed ring non-isomerizable analogs, or other analogs resistant to conversion to metabolite E (a full estrogen), still resulted in tumor growth stimulation. Growth of these tamoxifen-stimulated tumors was inhibited by a pure steroidal antiestrogen, ICI 182,780, suggesting that this drug should be investigated in patients with tamoxifen resistance. These tamoxifen-stimulated tumors could be further stimulated by estrogen replenishment, and estrogen stimulation was blocked by tamoxifen, indicating that tamoxifen has both agonist and antagonist properties in these tumors. Our data suggest that although tamoxifen-stimulated tumors display a markedly altered metabolite profile, isomerization or metabolism of tamoxifen does not fully explain the development of tamoxifen-stimulated growth. The mechanisms by which tamoxifen acquires more potent in vivo agonist properties over time remains to be defined.
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PMID:Mechanisms for tamoxifen resistance in breast cancer: possible role of tamoxifen metabolism. 827 45

Our recent retrospective analysis of the clinical records of patients who had breast thermography demonstrated that an abnormal thermogram was associated with an increased risk of breast cancer and a poorer prognosis for the breast cancer patient. This study included 100 normal patients, 100 living cancer patients, and 126 deceased cancer patients. Abnormal thermograms included asymmetric focal hot spots, areolar and periareolar heat, diffuse global heat, vessel discrepancy, or thermographic edge sign. Incidence and prognosis were directly related to thermographic results: only 28% of the noncancer patients had an abnormal thermogram, compared to 65% of living cancer patients and 88% of deceased cancer patients. Further studies were undertaken to determine if thermography is an independent prognostic indicator. Comparison to the components of the TNM classification system showed that only clinical size was significantly larger (p = 0.006) in patients with abnormal thermograms. Age, menopausal status, and location of tumor (left or right breast) were not related to thermographic results. Progesterone and estrogen receptor status was determined by both the cytosol-DCC and immunocytochemical methods, and neither receptor status showed any clear relationship to the thermographic results. Prognostic indicators that are known to be related to tumor growth rate were then compared to thermographic results. The concentration of ferritin in the tumor was significantly higher (p = 0.021) in tumors from patients with abnormal thermograms (1512 +/- 2027, n = 50) compared to tumors from patients with normal thermograms (762 +/- 620, n = 21). Both the proportion of cells in DNA synthesis (S-phase) and proliferating (S-phase plus G2M-phase, proliferative index) were significantly higher in patients with abnormal thermograms. The expression of the proliferation-associated tumor antigen Ki-67 was also associated with an abnormal thermogram. The strong relationships of thermographic results with these three growth rate-related prognostic indicators suggest that breast cancer patients with abnormal thermograms have faster-growing tumors that are more likely to have metastasized and to recur with a shorter disease-free interval.
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PMID:Breast thermography is a noninvasive prognostic procedure that predicts tumor growth rate in breast cancer patients. 827 54

Tamoxifen is the endocrine treatment of choice for breast cancer. However, resistance to therapy and patient relapse inevitably occurs. In future treatment schedules, interferons could be administered with tamoxifen, in an attempt to prevent disease recurrence. Human recombinant interferon-beta SER (rIFN-beta SER) inhibited the growth in vitro of the estrogen receptor (ER) positive breast cancer cell line MCF-7 and the ER negative breast cancer cell line MDA-MB-231. This inhibitory effect was achieved at doses of 50 U/ml and above. The growth of MCF-7 tumors in estradiol-stimulated athymic mice was greatly inhibited by high dose rIFN-beta SER treatment (10(6)U/day). In spite of the impressive antitumor effects upon MCF-7 tumors, rIFN-beta SER had no effect upon ER levels within the tumors at either the RNA or protein level, as measured by Northern blotting and ER-EIA respectively. High dose rIFN-beta SER (10(6)U/day) did result in some inhibition in the growth in vivo of the tamoxifen-stimulated MCF-7 variant MCF-7 TAM, although not to the same extent as was observed with the estradiol-stimulated MCF-7 tumors. rIFN-beta SER was also administered to animals bearing MCF-7 tumors and treated with estradiol and tamoxifen. In the animals undergoing high dose therapy (10(6)U/day), tumor growth was completely suppressed. Furthermore, tumor growth continued to be suppressed in those animals in which the rIFN-beta SER therapy was halted and the tamoxifen capsule removed. No tumors were observed in spite of the environment of estradiol stimulation. Thus, the combination of interferon and tamoxifen was totally growth suppressive for MCF-7 xenografts in nude mice.
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PMID:Human recombinant interferon-beta SER and tamoxifen: growth suppressive effects for the human breast carcinoma MCF-7 grown in the athymic mouse. 834 46

Estrogen hormones are known to exert a complex influence on development and function of the female reproductive organs of vertebrates by regulating cell growth and differentiation, as well as to be implicated in oncogenesis and maintenance of tumor growth. Estrogen acts on cells via interaction with an intracellular receptor, which, like all receptors for steroid hormones, is a trans-acting transcription enhancer factor activated by the cognate ligand and capable of binding to specific, cis-acting enhancer elements usually located within the 5'-flanking regions of target genes. Additionally, estrogen regulates gene expression by influencing mRNA stability or via interaction of the estrogen receptor with transcription regulatory factors. This article reviews data indicating that estrogen directly activates (primary activation) expression of proto-oncogenes codifying for nuclear proteins that, in turn, are responsible for indirect (secondary) activation of other genes. This cascade mechanism of gene activation is likely to progress for several more steps and allows us to envisage how estrogen can direct a complex task such as cell reproduction. Among proto-oncogenes codifying for nuclear proteins, we focus on fos, jun, myc, and related genes. The mechanisms of regulation of these genes by estrogen, including regulation of transcription, messenger RNA stabilization, and protein-protein interaction, are reviewed.
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PMID:Estrogen regulation of proto-oncogenes coding for nuclear proteins. 835 38

Three hundred and thirteen cases of human thyroid tissues, comprising 39 nodular goiters from 34 females and 5 males, 130 adenomas from 93 females and 37 males, and 144 carcinomas from 99 females and 45 males were used for the present immunohistochemical assessment of estrogen receptor (ER) expression. Thirty-three cases of follicular carcinoma, 115 cases of papillary carcinoma and 6 cases of anaplastic carcinoma were included in the malignant tumor group. Incidences of ER-positive cases were 23/39 (58.9%) for nodular goiter, 44/130 (33.8%) for adenoma and 26/144 (18.0%) for cancer. In the individual carcinoma categories, 7/23 (30.4%) follicular, 19/115 (16.5%) papillary and 0/6 (0%) anaplastic lesions were judged as positive cases. Thus, the incidence of ER-positive cases tended to decrease with the degree of malignancy; this trend being similar in both sexes. Moreover, the average ages of ER-positive cases were lower than those of ER-negative cases for all types of thyroid carcinoma except the follicular variety in males. It was thus suggested that ER expression may be related to prognosis and tumor growth at early stage. Since the incidence of ER does not significantly differ between females and males, the observed sex differences regarding thyroid tumor incidence may reflect the higher estrogen serum content in females.
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PMID:Immunohistochemical analysis of estrogen receptors in 313 paraffin section cases of human thyroid tissue. 845 Oct 35

The influence of estrogens and tamoxifen on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells transplanted into athymic nude mice was investigated. The mice were divided into the following three groups: (1) an E2 group with mice receiving 17 beta-estradiol dipropionate; (2) a TAM group with mice receiving tamoxifen; (3) a control group with mice given no hormone. (1) Tumor growth was significantly increased in the E2 group, but significantly decreased in the TAM group compared to control; (2) the tumor contents of insulin-like growth factor-I (IGF-I) and the rate of IGF-I-positive cells were significantly lower in the E2 group, but significantly higher in the TAM groups compared to control; (3) the IGF-I-positive cell rates were in significant inverse correlation with the [3H]thymidine-labeled cell rates in the E2, TAM and control groups. Thus, the tumor contents of IGF-I and the rate of IGF-I-positive cells were inversely correlated to the tumor growth and the [3H]thymidine-labeled cell rate in this in vivo study, although IGF-I is known to be a mitogen for breast cancer cells in vitro. Further studies are necessary to answer the questions as to the in vivo roles of immunoreactive IGF-I in ER-positive breast cancer.
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PMID:Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice. 847 69

The antitumor effect of 22-oxa-calcitriol (OCT), a newly developed noncalcemic analogue of calcitriol, was examined in vivo in athymic mice implanted with human breast carcinoma with or without estrogen receptor (ER). In ER-positive MCF-7 tumor, the growth of which was dependent on exogenous estrogen, administration p.o. of OCT as well as the antiestrogen tamoxifen five times a week for 4 weeks suppressed tumor growth in a dose-related fashion. The antitumor effect of 1.0 microgram/kg body weight (BW) OCT (mean +/- SEM of tumor weight in 6 mice: 28 +/- 4% of vehicle-treated group) was comparable to that of 2.0 mg/kg BW tamoxifen (25 +/- 6% of control group). In addition, a synergistic antitumor effect of submaximal doses of OCT and tamoxifen was observed in MCF-7 tumor in vivo as well as in ER-positive breast carcinoma cell lines (MCF-7 and ZR-75-1) in vitro. Administration of OCT p.o. three times a week for 4 weeks also suppressed the growth of ER-negative MX-1 tumor in a dose-dependent manner without raising serum calcium concentrations. The antitumor effect of 1.0 microgram/kg BW OCT (mean +/- SEM of tumor weight in 10 mice: 44 +/- 6% of vehicle-treated group) was greater than that of 500 micrograms/kg BW Adriamycin (71 +/- 6% of control group). These results indicate that OCT suppresses the growth of ER-negative as well as ER-positive breast carcinoma in vivo without causing hypercalcemia and that the antitumor effect of OCT can be enhanced by tamoxifen in an ER-positive tumor. It is suggested that OCT may provide a new strategy, either alone or in combination with other anticancer drugs, for systemic adjuvant therapy of breast carcinoma regardless of ER status.
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PMID:Antitumor effect of 22-oxa-calcitriol, a noncalcemic analogue of calcitriol, in athymic mice implanted with human breast carcinoma and its synergism with tamoxifen. 849 16

Several laboratories have described estrogen receptor mRNA variants created by skipping internal exons. Some of the putative proteins encoded for by these variants have been functionally characterized by transfection analyses. The variant lacking exon 5 would lead, if translated, to a truncated receptor which shows dominant positive transactivation activity in the absence of hormone. It has been postulated that the variant could account for anti-estrogen resistant tumor growth and for expression of the progesterone receptor in estrogen negative tumors. In order to understand the possible role this and other variants may have in the tumorigenesis of mammary tissue we have carried out a thorough analysis of variants expressed in a tumor cell line (MCF-7), in a tumor sample and in a sample of normal breast tissue derived from mammary reduction surgery. We performed rt-PCR analyses followed by hybridization with exon specific oligonucleotide probes. By these means we have detected nine different variants co-expressed in MCF-7 cells and at least the major variants were equally expressed in normal and neoplastic breast tissue. The same is true for the variant lacking exon 5 which, however, resulted to be a variant of low expression in the three samples analyzed. Variant formation appeared to be restricted to the estrogen receptor messenger since several other members of the superfamily of nuclear receptors did not show variant formation. We also have analyzed the effect of the most abundantly expressed variant, the exon 4 lacking variant, on normal estrogen receptor function, on the growth and on the response to estradiol and to tamoxifen of MCF-7 cells. Although over-expressed at high levels this variant has, if any, only marginal effects on the expression of endogenous estrogen regulated genes and on growth and response to the hormone and its antagonist. Although the lack of function of this variant cannot be extrapolated to other variants, their involvement in tumor formation appears rather unlikely since they are also expressed in normal tissue and the single variant is expressed in addition to many others, some of which might have opposing effects. Variant formation is, however, specific for the estrogen receptor and apparently regulated with tissue specificity as our expression analysis in normal mouse tissues shows. Therefore the variants probably have a physiological significance yet to be discovered.
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PMID:Alternative splicing of the estrogen receptor primary transcript normally occurs in estrogen receptor positive tissues and cell lines. 860 53

A significant change of vitamin E and malondialdehyde plasma concentrations was reported in breast cancer patients. This change was unexpected because vitamin E was higher and malondialdehyde lower in cases than in controls, and the difference was more significant in young rather than older women. The first aim of this study was to determine whether these changes were associated only with breast cancer, or with hormone-related cancers, and/or cancers associated with nutritional risk factors or with all types of cancers. Measurements were performed before therapy on 269 hospital-based controls and on 146 patients with various carcinomas. Vitamin E:total cholesterol increased and malondialdehyde plasma concentration decreased with tumor size and progression, without relation to the site. The second aim was to understand the difference in the change observed between young and old breast cancer patients. These analytes were measured in 365 breast cancer patients according to three prognosis factors: pathology, tumor size and estrogen receptors. Vitamin E:total cholesterol significantly decreased with estrogen receptor amount. Malondialdehyde plasma concentration decreased with severity of pathology and tumor size. Together, these data support the association of an altered oxidant-antioxidant profile in cancer patients with tumor growth and progression.
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PMID:Oxidant-antioxidant status alterations in cancer patients: relationship to tumor progression. 864 57

Endocrine therapy of mammary and prostate cancer has been established for decades. The therapies available to block sex-hormone-receptor-mediated tumor growth are based on two principles: (i) ligand depletion, which can be achieved surgically, by use of luteinizing-hormone-releasing hormone analogues or inhibitors of enzymes involved in steroid biosynthesis or by interfering with the feedback mechanisms of sex hormone synthesis at the pituitary/hypothalamic level; (ii) blockade of sex hormone receptor function by use of antihormones. The antiestrogen tamoxifen, which is the compound of choice for the treatment of mammary carcinoma, has the drawback of being a partial agonist. A complete blockade of estrogen receptor (ER) function can be achieved by a new class of compounds, pure antiestrogens. In contrast to aromatase inhibitors, pure antiestrogens are able to block ER activation by ligands other than estradiol and can also interfere with ligand-independent ER activation. In addition to estradiol, progesterone has a strong proliferative effect in mammary carcinomas. Antiprogestins are promising new tools for clinical breast cancer therapy. These compounds clearly need a functionally expressed progesterone receptor to block tumor growth, but there is strong experimental evidence that their tumor inhibition is based on more than just progesterone antagonism. The ability of these compounds to induce tumor cell differentiation that leads to apoptosis is unique among all other endocrine therapeutics. In prostate tumors that have relapsed from current androgen-ablation therapies the androgen receptor (AR) is still expressed and, compared to the primary tumors, its level is often even enhanced. Mutated AR that can be activated by other compounds such as adrenal steroids, estrogens, progestins and even antiandrogens have been detected in recurrent tumors. Thus, relapse of tumors under the selective pressure of common androgen-ablation therapies can be caused by acquired androgen hypersensitivity and AR activation by ligands other than (dihydro-)testosterone. There is a clinical need for future compounds that produce a complete blockade of AR activity even in recurrent tumors. Preclinical experiments indicate that combination therapy as well as the extension of endocrine treatments to several other tumor entities are promising approaches for further developments. Examples are the combination of antiestrogens and antiprogestins for breast cancer treatment, or the treatment of prostate carcinomas with antiprogestins.
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PMID:The future of antihormone therapy: innovations based on an established principle. 869 Jul 48


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