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PubMed2000

Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival.

Tumor associated macrophages (TAM) influence diverse processes such as angiogenesis, tumor cell proliferation, and metastasis during tumor progression. In a variety of tumor types, the amount of TAM has been associated with prognosis, but their role in prostate cancer has not been elucidated. The purpose of this study was to investigate the role of TAM in a series of 85 cases of prostatic carcinoma, diagnosed at transurethral resection of the prostate between 1975-1983, using immunohistochemistry and morphometrical techniques. Macrophage density was assessed as the maximum number of TAM per field in the three most macrophage dense areas (TAMmax) and as the average volume density of TAM in an estimate of the whole resected tumor. Furthermore, the individual cell profile area of TAM was assessed with an image analyzer. Macrophage variables were thereafter related to histological grade, tumor stage, metastasis as well as to vascular density, tumor cell proliferation and survival. Patients with a volume density of TAM in the fourth quartile had a shorter median cancer specific survival time than patients in the first to third quartile (3.3 vs. 5.9 years, p=0.005). Furthermore, an increased macrophage cell profile area was related to poor clinical outcome (4.6 vs. 5.9 years, p=0.039) whereas TAMmax gave no prognostic information. In a multivariate analysis, metastasis and the volume density of macrophages gave independent prognostic information (p=0.0008, p=0.010). However, when excluding metastasis from the analysis, only Gleason score was an independent predictor of cancer specific survival (p= 0.005). The volume density of TAM, the macrophage cell profile area and TAMmax increased with increasing Gleason score (p=0.001, p=0.0001, p=0.0001 respectively). A correlation was found between the volume density of TAM and tumor cell proliferation (rs=0.44, p=0.001) and an increased macrophage cell profile area was associated to microvessel density (rs=0.42, p=0.0001). Together these results suggest that both the functional state (as reflected by cell size), number and location of the macrophages are of importance for their influence on prostate tumors, but macrophage quantification is not a strong independent prognostic factor.

Adenocarcinoma↗
PubMed2005

Hepatoprotective effect of green tea (Camellia sinensis) extract against tamoxifen-induced liver injury in rats.

Tamoxifen citrate (TAM), is widely used for treatment of breast cancer. It showed a degree of hepatic carcinogenesis. The purpose of this study was to elucidate the antioxidant capacity of green tea (Camellia sinensis) extract (GTE) against TAM-induced liver injury. A model of liver injury in female rats was done by intraperitoneal injection of TAM in a dose of 45mg Kg(-1) day(-1), i.p. for 7 successive days. GTE in the concentration of 1.5 %, was orally administered 4 days prior and 14 days after TAM-intoxication as a sole source of drinking water. The antioxidant flavonoid; epicatechin (a component of green tea) was not detectable in liver and blood of rats in either normal control or TAM-intoxicated group, however, TAM intoxication resulted in a significant decrease of its level in liver homogenate of tamoxifenintoxicated rats. The model of TAM-intoxication elicited significant declines in the antioxidant enzymes (glutathione-S-transferase,glutathione peroxidase, superoxide dismutase and catalase) and reduced glutathione concomitant with significant elevations in TBARS (thiobarbituric acid reactive substance) and liver transaminases; sGPT (serum glutamate pyruvate transaminase) and sGOT (serum glutamate oxaloacetate transaminase) levels. The oral administration of 1.5 % GTE to TAM-intoxicated rats, produced significant increments in the antioxidant enzymes and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases levels. The data obtained from this study speculated that 1.5 % GTE has the capacity to scavenge free radical and can protect against oxidative stress induced by TAM intoxication. Supplementation of GTE could be useful in alleviating tamoxifen-induced liver injury in rats.

Animals↗
PubMed2000

Pharmacodynamics of tamoxifen and its 4-hydroxy and N-desmethyl metabolites: activation of caspases and induction of apoptosis in rat mammary tumors and in human breast cancer cell lines.

The antiestrogen tamoxifen (TAM) is extensively metabolized by cytochrome P-450 in humans and rodents. The active, estrogen receptor-binding metabolites, 4-hydroxy TAM (OHT) and N-desmethyl TAM (DMT) have been well characterized. We showed that the s.c. injection of 1 mg/kg TAM in adult female Sprague Dawley rats bearing carcinogen-induced mammary tumors resulted in rapid serum decline of parent TAM but higher exposure of the metabolites, OHT and DMT. We found for the first time that the administration of TAM for a short time resulted in a delayed induction of caspase activity and apoptosis within the mammary tumors. When TAM, OHT, or DMT was added to human breast cancer cell lines in culture, each elicited a time- and dose-dependent induction of caspase activity, preceding apoptosis. Importantly, pretreatment of the cells with a pharmacological inhibitor of caspases [benzyloxy Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk)] blocked apoptosis induced by all three of the compounds, implicating a critical role of caspases in TAM-, OHT-, or DMT-induced apoptosis. The results obtained from these studies suggest that one possible mechanism of inhibition of mammary carcinogenesis and tumor growth in vivo may be the induction of caspase-dependent apoptosis, and that the metabolites OHT and DMT may contribute to the antitumor effect of TAM.

Animals↗
PubMed2002

Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice.

The use of dietary isoflavone supplements by postmenopausal women with breast cancer is increasing. We investigated interactions between the soy isoflavone, genistein, and an antiestrogen, tamoxifen (TAM), on the growth of estrogen (E)-dependent breast cancer (MCF-7) cells implanted in ovariectomized athymic mice. We hypothesized that weakly estrogenic genistein negate/overwhelm the inhibitory effect of TAM on the growth of E-dependent breast tumors. Six treatment groups were used: control (C); 0.25 mg estradiol (E2) implant (E); E2 implant + 2.5 mg TAM implant (2.5 TE); E2 implant + 2.5 mg TAM implant + 1000 ppm genistein (2.5 TEG); E2 implant + 5 mg TAM implant (5 TE), and E2 implant +5 mg TAM implant +1000 ppm genistein (5 TEG). Treatment with TAM (2.5 TE and 5 TE) suppressed E2-stimulated MCF-7 tumor growth in ovariectomized athymic mice. Dietary genistein negated/overwhelmed the inhibitory effect of TAM on MCF-7 tumor growth, lowered E2 level in plasma, and increased expression of E-responsive genes (e.g., pS2, PR, and cyclin D1). Therefore, caution is warranted for postmenopausal women consuming dietary genistein while on TAM therapy for E-responsive breast cancer.

Animals↗
PubMed2003

Induction of antiproliferation and apoptosis in estrogen receptor negative MDA-231 human breast cancer cells by mifepristone and 4-hydroxytamoxifen combination therapy: a role for TGFbeta1.

Mifepristone (MIF) is an antiprogestin with potent anti-glucocorticoid and anti-androgen activity. MIF also appears to have anti-tumor activity independent of its ability to bind to nuclear receptors. In this study, we tested the ability of MIF to inhibit the growth of ER and PR negative breast cancer cells. In addition, because high-dose anti-estrogen treatment has been shown to inhibit ER and PR negative breast cancer cells, we compared the anti-proliferative activity of MIF to that of the anti-estrogen 4-hydroxytamoxifen (TAM) or combination hormonal therapy (MIF + TAM). MIF and TAM therapy induced a significant time- and dose-dependent growth inhibition and, ultimately, induced cell death in MDA-231 cells as evidenced by increased DNA fragmentation, cytochrome c release from the mitochondria, and the activation of caspase-3. The anti-proliferative activity of TAM plus MIF combination treatment was at least additive as compared to either monotherapy. The earliest indicator of TAM and MIF cytostatic and cytotoxic action on MDA-231 cells was a significant (p<0.05) induction of TGFbeta1 secretion into the growth medium within 4 h of treatment. Secreted TGFbeta1 levels at 24 and 48 h were significantly higher in the TAM plus MIF treatment group as compared to cells treated with TAM or MIF alone. TGFbeta1 neutralizing antibody or addition of mannose-6-phosphate (M6P), a reagent also used to inhibit TGFbeta1, significantly attenuated the TAM and/or MIF-induced cell growth inhibition and cell death. In summary, our results indicate that MIF used in combination with TAM can effectively kill estrogen-insensitive human breast cancer cells. Our study further implies that agents that effectively increase TGFbeta1 levels in ER negative breast cancer cells may be one treatment approach for hormone-independent breast cancers.

Apoptosis↗
PubMedDate not supplied

The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients.

BACKGROUND: Tumor-associated macrophages (TAMs) have varying functions depending on the microenvironment of tumor tissue. We studied the biological role of TAMs in gastric cancer on the basis of their spatial distribution in the cancer tissue. MATERIALS AND METHODS: Tissue specimens from 84 advanced gastric carcinoma (pT2; 41 cases, pT3; 43 cases) patients who had undergone a curative resection were stained for TAM (CD68+ cells), incidence of tumor cell apoptosis (TUNEL) and host immune status (CD8+ T cells). CD68+ and CD8+ T cells infiltrated into the cancer cell nests or in close contact with cancer cells were considered as nest TAMs and nest CD8, respectively. RESULTS: Nest TAMs had a very strong direct correlation with frequency of tumor cell apoptosis (p < 0.0001) and degree of nest CD8 (p = 0.0004). The 5-year disease-free survival rate in the high-nest TAM category (87%) was significantly higher than in the low-nest TAM group (44%) (p = 0.0002). Among the several prognostic factors, nest TAM, nest CD8 and pT stage became independent predictors of patient survival (p = 0.016, p = 0.001 and p = 0.029, respectively) in Cox's multivariate analysis. CONCLUSION: These results suggested that the aggregation of TAMs within tumor nest had a beneficial effect on host in terms of augmented cytotoxicity and antigen presentation.

Adenocarcinoma↗
PubMedDate not supplied

Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer.

BACKGROUND: To clarify the pathophysiological role of tumor-associated macrophages (TAMs), we performed clinicopathological analysis of CD68+ cells in 70 cases of human endometrial cancer. MATERIALS AND METHODS: Using immunohistochemistry for CD68, we classified CD68+ cells into four groups: (a) those infiltrated into cancer cell nests or in close contact with cancer cells (nest TAM); (b) those in necrosis in the tumor center (hot-spot TAM); (c) those infiltrated into cancer stroma (stroma TAM); and (d) those distributed along the invasive margin of a tumor (Margin TAM). RESULTS: The aggregation of nest TAM related to high relapse-free survival rate after surgery. On the contrary, increased hot-spot TAM was a hazard to relapse-free survival and was proportionately-associated with clinical stage, myometrial invasion and histological differentiation. The extent of stroma TAM was associated with the presence of lymph node metastasis. CONCLUSION: Our findings demonstrate that the histological location of infiltrated TAMs may be taken into account in the clinical evaluation of endometrial cancer.

Adult↗
PubMed2005

Combination of 5-deoxy-5-fluorouridine and tamoxifen show cell-type specific antagonistic and cooperative effects on cytotoxicity in human mammary carcinoma cells.

The effect of tamoxifen (Tam) and 5-deoxy-5-fluorouridine (5-DFUR) cotreatment on cytotoxicity was assessed in various cancer-derived cell lines. Each cell line was treated with a range of Tam and 5-DFUR concentrations alone and in combination. The cell lines we examined include MDA-MB-231 (ERalpha-/ERbeta+), T47D (ERalpha+/ERbeta+), and three MCF-7 (ERalpha+/ERbeta+) sublines. Cell growth was assessed by MTT assay at multiple time points for up to 9 days. Fluorescence-associated cell sorting (FACS) analysis was used to examine the effects of Tam and 5-DFUR cotreatment on cell cycle progression. Treatment with Tam or 5-DFUR, which is metabolized to 5-FU in target cells, produced an anti-proliferative effect that was dose- and time-dependent in all cell lines examined; variation in cell line sensitivity to each compound and cotreatment was apparent. When 5-DFUR and Tam treatment were combined, T47D, MDA-MB-231, and an MCF-7 subline demonstrated a cooperative effect at the lowest Tam concentration tested in 9-day cultures. The significance of treatment dosage and duration was obvious when 5-DFUR and Tam cotreatment was observed to be antagonistic in 3-day cultures of a second MCF-7 subline and T47D cells. Results from our studies show that there may be cytotoxic benefits in the treatment of cancer from combined therapy with Tam and 5-FU precursor drugs. Enhanced inhibition of proliferation was observed when Tam was cotreated at low concentrations in relatively long-term cultures. This has clinical relevance in that it suggests that patients undergoing chemo-endocrine therapy with orally administered 5-FU precursor drugs may benefit from lower treatment dosages relative to other adjuvant therapies.

Antineoplastic Agents↗
PubMed2006

[Influence of tumor-associated macrophages on progression and prognosis of nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Tumor-associated macrophages (TAMs) density is negatively correlated to prognosis of lung cancer, breast cancer, and so on, and positively correlated to prognosis of gastric cancer and some colorectal cancer. This study was to investigate the influence of TAMs on the progression and prognosis of nasopharyngeal carcinoma (NPC). METHODS: Immunohistochemistry was adopted to detect the expression of CD68, a marker of TAMs, in 60 specimens of NPC. Macrophages were cocultured respectively with supernatant liquid of NPC cell lines CNE-1 and CNE-2 and lung cancer cell line 95D for 1 day or 6 days, and then activated by LPS for 1 day. The expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), secreted by TAMs after coculture of TAMs and supernatant liquid of NPC cell lines CNE-1 and CNE-2, was detected by ELISA. The macrophages co-cultured with supernatant of lung cancer cell line 95D was used as positive control; normal macrophages were used as negative control. RESULTS: The 3-year tumor-freely survival rate was significantly higher in high TAMs density group than in low TAMs density group (85.7% vs. 56.3%, P<0.05). After coculture, the expression levels of TNF-alpha and IL-10 in supernatant were lower in CNE-1 group and CNE-2 group than in 95D group (73 pg/ml, 64 pg/ml vs. 7,794 pg/ml, P=0.001; 1 pg/ml, 1 pg/ml vs. 94 pg/ml, P=0.002); after LPS activation, the expression levels of TNF-alpha and IL-10 were higher in CNE-1 group and CNE-2 group than in 95D group (6,905 pg/ml, 6,788 pg/ml vs. 137 pg/ml, P=0.001; 87 pg/ml, 99 pg/ml vs. 416 pg/ml, P=0.015). But the difference between NPC cell lines and normal macrophages was not significant. CONCLUSIONS: TAMs density is positively correlated to the prognosis of NPC. The cytokines secreted by TAMs trend to kill tumor cells and promote antitumor immune response.

Adolescent↗
PubMed1989

[Experimental multihormone therapy on human breast carcinomas grown in nude mice].

Experimental multihormone therapy with tamoxifen (TAM), aminoglutethimide (AMG) and medroxyprogesterone acetate (MPA) was investigated using three hormone-dependent human breast carcinomas serially transplanted into nude mice. TAM was the most effective of these agents, showing an efficacy rate of 100%, whereas MPA was the least effective, showing an efficacy rate of only 17%. The combination treatment of TAM and AMG was more effective than that of either TAM or AMG used alone. The antitumor effect of TAM was considered to be related to the changes of the hormone receptor levels. Since AMG significantly reduced the estrogen level and the uterine weight in normal female mice, the antitumor effect of combined TAM and AMG was assumed to be a result of the low estrogen level caused by AMG, enhancing the ability of TAM to compete with estrogen receptors. There was no additional antitumor effect of the combination of TAM and MPA, although serum MPA levels in mice were almost equivalent to those in humans who were treated with 1200mg of MPA po daily. These results indicated that combination hormone therapy, particularly with TAM and AMG, might be a promising method for the clinical treatment of human breast cancer.

Aminoglutethimide↗
PubMed1989

Enhanced growth of an estrogen receptor-negative endometrial adenocarcinoma by estradiol in athymic mice.

The aim of this study was to investigate the effects of estradiol and tamoxifen (TAM) on the growth of human endometrial carcinomas in athymic mice. Tissues from primary tumors were implanted into estradiol-treated mice. In passage 2, animals were treated with (a) placebo, (b) estradiol, (c) estradiol plus TAM, and (d) TAM alone. The size of the tumors was measured weekly. Estrogen receptors (ER) were determined with the dextran-coated charcoal method and/or ER enzyme-linked immunoassay. Progesterone receptors were measured with the dextran-coated charcoal technique. Of 16 primary tumors, 2 grew in the athymic mice and were studied further. Tumor EL was positive for ER (145 fmol/mg protein) and progesterone receptors (993 fmol/mg protein). Tumor EL in passage 2 was not significantly stimulated by estradiol, but was stimulated by a combination of estradiol and TAM. Treatments (estradiol, estradiol plus TAM, or TAM) all increased tumor growth in passage 3. Tumor BR and a metastasis BR-MET were ER and progesterone receptor negative, applying dextran-coated charcoal, ER enzyme-linked immunoassay, and immunocytochemistry. The BR and BR-MET cells contain the complete ER gene but do not express any measurable amounts of ER mRNA as quantitated by Northern blot analysis, using a complete ER complementary DNA probe. In all animal passages the growth rate was significantly higher in estradiol-treated mice compared with the control. TAM alone had some growth stimulatory effect, but much smaller than observed in the estradiol group. TAM inhibited estradiol-stimulated growth. These results suggest that estradiol and possibly TAM are capable of stimulating tumor growth in the athymic mice independently from ER, potentially through a host-mediated mechanism.

Adenocarcinoma↗
PubMed1988

Involvement of the polyamine pathway in antiestrogen-induced growth inhibition of human breast cancer.

Recent evidence indicates that the antiestrogen tamoxifen (TAM) may inhibit breast cancer cell proliferation, at least in part, through suppression of the polyamine (PA) pathway. To directly test this hypothesis, we evaluated the effect of TAM administration on ornithine decarboxylase (ODC) activity, the rate-limiting enzyme in PA synthesis, as well as cellular PA levels in the hormone-responsive MCF-7 breast cancer cell line in culture. In detailed time course studies, we observed that TAM significantly inhibited the rise in ODC activity observed in control cells following a medium change. Chronic treatment with escalating amounts of TAM caused a dose-related decrease in tumor pools of putrescine and spermidine, while spermine levels were unaffected. The TAM effects on ODC activity and PA pools were reversible with exogenous estradiol administration. However, addition of putrescine to TAM-treated cells did not result in a reversal of the antiproliferative effect of TAM, despite repletion of cellular PA pools. Administration of TAM to the hormone-independent MDA-MB-231 breast cancer cell line did not suppress ODC activity or cellular PA levels despite induction, at high concentrations, of an estradiol-irreversible inhibition of proliferation. We conclude that, in the hormone-responsive MCF-7 breast cancer cell line, TAM causes a significant suppression of the PA pathway, the relation of which, if any, to its antiproliferative action remains obscure. This effect seems to be mediated through the estrogen receptor and does not appear to be a nonspecific consequence of inhibition of cell proliferation.

Biogenic Polyamines↗
PubMed1995

Effects of norethisterone acetate and tamoxifen on serum prolactin levels, uterine growth and on the presence of uterine immunoreactive prolactin in estradiol-treated ovariectomized rats.

The aim of the present work was to study the effects of the antiestrogen tamoxifen (TAM), of progestin norethisterone acetate (NA) and of their combination on serum prolactin levels, uterine growth and the presence of uterine immunoreactive prolactin in estradiol-treated rats. Ovariectomized female Wistar rats were injected sc with estradiol valerate (VE, 50 micrograms/rat per week) or oil vehicle. During the second week, estradiol-treated rats also received NA (0.12 or 1.0 mg/rat, sc, daily) or TAM (0.06 mg/rat) alone or in combination with NA (0.12 mg). Serum prolactin levels were suppressed to the same extent in the TAM- and 1.0 mg NA-treated groups compared with rats given estrogen alone (2.3 +/- 0.3 and 5.6 +/- 1.5 ng/ml for TAM and NA groups vs 39.7 +/- 3.6 ng/ml for VE groups, P < 0.05). Except for the lowest dose of NA, uterine wet weight and DNA content were significantly reduced in all groups compared to estradiol alone (236.8 +/- 18.0 and 295.6 +/- 27.8 mg vs 309.4 +/- 32.2 mg for uterine weight in TAM and NA groups vs VE, respectively, P < 0.05; and 1.14 +/- 0.05 and 0.93 +/- 0.04 mg/uterus vs 1.33 +/- 0.06 mg/uterus for uterine DNA in TAM and NA groups vs VE groups). The combination of NA and TAM resulted in a higher degree of suppression of uterine growth than when each drug was used alone, indicating an additive antiproliferative effect of NA and TAM. Although no prolactin immunostaining was detected in the uterus of rats treated with estradiol, uterine immunoreactive prolactin was identified in those treated with NA, TAM or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effect of aromatase inhibitors on growth of mammary tumors in a nude mouse model.

The effects of aromatase inhibitors 4-hydroxyandrostenedione (4-OHA), CGS 16949A, and CGS 20267, and of the antiestrogen tamoxifen (TAM), were studied on the growth of human breast carcinoma in a nude mouse model. To simulate the postmenopausal breast cancer patient, tumors were formed from inoculates of MCF-7 cells transfected with the human aromatase gene to provide a source of non-ovarian estrogen in ovariectomized mice. Tumor growth was significantly inhibited by all treatments (P < 0.05). Greater reduction in growth occurred in mice treated with TAM combined with aromatase inhibitors than with TAM alone. Tumor progesterone receptor concentrations were unaltered by TAM treatment but were reduced by aromatase inhibitors. Progesterone receptor concentrations correlated with tumor growth. The greatest reduction occurred in tumors of CGS 20267-treated mice in which no progesterone receptors were detected. In the ovariectomized mice used in these studies, uterine weight was maintained by estrogen produced from the tumor. Uterine weight was reduced by aromatase inhibitors but not by TAM treatment. However, there was a significant increase in uterine weight in mice treated with the combination of TAM and 4-OHA. Thus, the agonist effect of TAM was evident when estrogen synthesis was inhibited. The results indicate that aromatase inhibitors have potent effects on mammary tumor growth but lack the estrogenic effects on the uterus observed with TAM. There appeared to be no significant benefit in combining TAM with 4-OHA over 4-OHA treatment alone.

Androstenedione↗
PubMed1994

Mechanism of action of a dominant-negative mutant of c-Jun.

The AP-1 transcriptional activating complex, made up of Jun and Fos protein, is involved in controlling many cellular processes such as cell proliferation, differentiation and transformation. We have previously characterized a dominant-negative mutant of c-Jun called TAM-67 which forms dimers with c-Jun and c-Fos, and binds DNA as a homodimer or heterodimer with c-Jun or c-Fos. This dominant-negative mutant is a potent inhibitor of AP-1 mediated transactivation, as well as c-jun/ras and TPA/ras-induced transformation. The present report describes experiments designed to elucidate the exact molecular mechanism of this dominant-negative inhibitor. The DNA binding kinetics of both TAM-67:TAM-67 homodimers as well as TAM-67:Fos heterodimers were studied and compared to those of c-Jun and other transactivation-deficient mutants of c-Jun. These studies demonstrated that the TAM-67 proteins have similar DNA binding kinetics to c-Jun and other Jun mutant proteins. Thus, the deletion of the amino-terminal end of the Jun protein does not significantly alter the protein's affinity for DNA. In addition, to determine whether TAM-67 functions through the formation of homodimers, or through interactions with endogenous c-Jun or c-Fos, we constructed a pair of chimeric proteins made by replacing the leucine zipper of TAM-67 with the leucine zippers of GCN4 and c-Fos. These chimeric proteins, termed TAM/GCN4 and TAM/Fos, were then tested for their ability to bind DNA, inhibit c-Jun-induced transactivation, and inhibit TPA/ras-mediated transformation. The results of these studies show that while both chimeric proteins bind equally well to DNA, only the TAM/Fos protein, and not the TAM/GCN4 protein, inhibits AP-1-induced transactivation and TPA/ras-induced transformation. When compared to the TAM-67 protein, the TAM/Fos protein is an equally potent inhibitor of transactivation and transformation. These results suggest that TAM-67 inhibits AP-1-mediated processes through a 'quenching' mechanism by inhibiting the function of endogenous Jun and/or Fos proteins. The implications of these mechanistic findings on the development of potent inhibitors of signal transduction pathways are discussed.

Animals↗
PubMed1994

Can plasma prolactin predict tamoxifen resistance in patients with advanced breast cancer?

The antiestrogen tamoxifen (TAM) is an effective therapy for advanced breast cancer. However, its use is limited by the eventual development of acquired TAM resistance in many patients. There is now strong evidence to suggest that prolactin plays an important role in advanced breast cancer. We have measured plasma prolactin (PRL) and estrogen-receptor (ER) and progesterone-receptor (PR) in post-menopausal patients with breast cancer (Stage III, n = 44). The blood samples were collected pre-operatively and sequentially thereafter for a minimum period of 3 years or until the death of the patients. The ER and PR were estimated in breast tumor samples by dextran-coated charcoal (DCC) method. The patients were treated with surgery and radiotherapy followed by TAM (10 mg, 1 BD). Based on the response to treatments, the patients were divided into two groups: (1) TAM sensitive (n = 19) and (2) TAM resistant (n = 25). In the TAM sensitive group, patients responded to the treatment and did not develop progressive disease within a period of 3 years. On the contrary, in the group of TAM resistant, patients developed progressive disease within a period of 3 years. The development of progressive disease clearly indicated TAM resistance. Plasma PRL correlated well with the disease progression. This study clearly demonstrated that plasma prolactin accurately indicated the response and development of resistance to TAM in patients with advanced breast cancer.

Breast Neoplasms↗
PubMed1996

The inhibitory activity of a transdominant c-jun mutant fused to the ligand binding domain of the estrogen receptor.

Tam-67 is an amino-terminal deletion mutant of c-Jun (delta3-122) lacking most of the c-Jun transactivation domain, which has been shown previously to function in a transdominant fashion to inhibit c-Jun-induced transactivation and cellular transformation. In order to create a ligand-dependent dominant negative repressor of AP-1, we have constructed a fusion of the TAM-67 gene with the ligand binding domain of the estrogen receptor. Fusion of TAM-67 with the ligand binding domain of the estrogen receptor produced a 68 kD protein (TAM-67ER) which was immunoprecipitated by c-Jun-specific and estrogen receptor-specific antisera and shown by gel retardation assay to bind oligonucleotides containing an AP-1 sequence. Cotransfection of TAM-67ER and an AP-1-dependent reporter construct into rat embryo cells demonstrated ligand specific inhibition of AP-1 transactivation. In the absence of hormone, TAM-67ER produced complete inhibition of c-Jun-induced AP-I transactivation. This inhibition was relieved by treatment with estradiol but not by treatment with tamoxifen. In addition, TAM-67ER inhibited activated c-Ha-ras- or c-raf-induced transformation of NIH3T3 cells. However, this inhibition of transformation was not relieved by the addition of estrogen. Thus, TAM-67ER inhibits transactivation in a ligand-dependent manner, but inhibits transformation in a ligand-independent manner. The results suggest that the ligand-dependent transactivation domain of the estrogen receptor (TAF-2) can substitute for the c-Jun transactivation domain absent in TAM-67 to stimulate transactivation. However, TAF-2 cannot substitute for the missing c-Jun transactivation domain to induce cellular transformation.

3T3 Cells↗
PubMed1997

Tamoxifen interferes with the insulin-like growth factor I receptor (IGF-IR) signaling pathway in breast cancer cells.

The insulin-like growth factor I receptor (IGF-IR) is involved in the control of breast cancer cell growth. The cytostatic activity of tamoxifen (Tam), a nonsteroidal antiestrogen, is partially mediated through interference with IGF-I-R-dependent proliferation, yet the effects of Tam on IGF-IR intracellular signaling have never been elucidated. Consequently, we investigated how Tam modifies the IGF-IR signaling pathway in estrogen receptor-positive MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR (MCF-7/IGF-IR cells) or its major substrate, IRS-1 (MCF-7/IRS-1 cells). MCF-7/IGF-IR and MCF-7/IRS-1 cells exhibit greatly reduced estrogen growth requirements but retain estrogen receptors and express sensitivity to antiestrogens comparable to that in the parental cells. In all tested cell lines, regardless of the amplification of IGF signaling, a 4-day treatment with 10 nM Tam produced a similar cytostatic effect. In MCF-7 and MCF-7/IGF-IR cells, growth inhibition by Tam was associated with the reduced tyrosine phosphorylation of the IGF-IR in the presence of IGF-I; however, the basal level of the IGF-IR remained unaffected. Moreover, Tam inhibited both basal and IGF-I-induced tyrosine phosphorylation of IRS-1, which was accompanied by down-regulation of IRS-1-associated phosphatidylinositol 3'-kinase activity and reduced IRS-1/growth factor receptor-bound protein 2 (GRB2) binding. In contrast, under the same treatment, tyrosine phosphorylation of Src-homology/collagen proteins (SHC; another substrate of the IGF-IR) and SHC/GRB2 binding were elevated. The protein levels of the IGF-IR and IRS-1 were not modified by Tam, whereas SHC protein expression was either not affected or moderately decreased by the treatment. In summary, this work provides the first evidence that in MCF-7 cells, cytostatic effects of Tam are associated with the modulation of IGF-IR signaling, specifically with: (a) down-regulation of IGF-I-induced tyrosine phosphorylation of the IGF-IR; (b) inhibition of IRS-1/phosphatidylinositol 3'-kinase signaling; and (c) up-regulation of SHC tyrosine phosphorylation and increased SHC/GRB2 binding. It is hypothesized that dephosphorylation of IRS-1 could be a major contributing factor in Tam cytostatic activity.

Adaptor Proteins, Signal Transducing↗