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PubMed2006

Distinct role of macrophages in different tumor microenvironments.

Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes.

Cell Movement↗
PubMed2000

Estrogen and tamoxifen differentially regulate beta-endorphin and cFos expression and neuronal colocalization in the arcuate nucleus of the rat.

Estrogen regulates hypothalamic gene expression, synthesis and release of the endogenous opioid peptide beta-endorphin (betaEND), although a consensus estrogen response element sequence has not been identified in the rat proopiomelanocortin (POMC) gene. POMC gene expression is also regulated by the activation of AP-1 promoter elements, which are known to be estrogen sensitive. The present studies examine whether estrogen modulates the hypothalamic POMC system through a non-classical mechanism involving AP-1 binding proteins such as cFos. Immunohistochemical double-labeling for betaEND and cFos was used and immunoreactive (-ir) populations were quantified in the arcuate nucleus and periarcuate area across time using unbiased stereological methods. Ovariectomized rats were injected with 50 microg estradiol (E2), 500 microg tamoxifen citrate (TAM) or both (E2+TAM) and were perfused 1, 2, 4 or 48 h later. E2 rapidly increased numbers of cFos-ir, betaEND-ir and doubly-labeled cells after 4 h, and the number of betaEND-ir cells remained high 48 h later, suggesting that the stimulatory effects of cFos on POMC in the hypothalamus persist after the cFos signal decays. Treatment with TAM alone did not affect the numbers of immunoreactive cells, although E2+TAM blocked the E2-mediated induction in all immunoreactive populations. Similar effects were seen at the transcriptional level. E2 increased hypothalamic POMC mRNA after 4 h, while TAM treatment or coadministration of E2+TAM did not significantly change the levels of POMC mRNA. Cellular colocalization of betaEND-ir and cFos-ir supports a possible intracellular co-regulation of these peptides by an estrogen-dependent mechanism within a subset of hypothalamic neurons. It does not, however, appear that E2 acts directly through an AP-1 site within the POMC gene.

Animals↗
PubMed2006

Expression of Bcl-2 and Ki-67 in tamoxifen-associated endometrial polyps: comparison with postmenopausal polyps.

BACKGROUND: The aim of this study was to evaluate the expression of Bcl-2 and Ki-67 in tamoxifen (TAM)-associated endometrial polyps and postmenopausal polyps. MATERIAL AND METHODS: For this purpose, a retrospective analysis of paraffin-embedded specimens was carried out. Polyps of 20 postmenopausal and 14 TAM-treated patients, 11 simple endometrial hyperplasia, 10 atypical complex endometrial hyperplasia and 8 endometrial adenocarcinoma specimens were included in the study. Hematoxylin/eosin-stained sections were evaluated. Immunohistochemical staining was performed to investigate the expression of Bcl-2 protein and the Ki-67 proliferation index. RESULTS: There was no statistically significant difference between the 5 groups with regard to Bcl- 2 staining (p > 0.05). However, Bcl-2 expression in TAM-associated polyps was higher (86%) than in the postmenopausal control group (80%). Positive Ki-67 was highest in the endometrial adenocarcinoma specimens, followed by the atypical complex endometrial hyperplasia group (p < 0.0001). Compared to these 2 groups, Ki- 67 expression was lower in TAM-associated polyps, but Ki-67 indexes were significantly higher in the TAM-associated group than in the control group (p < 0.0001). CONCLUSION: Since TAM-associated polyps tend to have higher proliferation indexes and Ki-67 ratios than control groups, we suggest that they are likely to have a higher malignant potential.

Endometrium↗
PubMed1987

Effects of brain antiestrogen implants on maternal behavior and on postpartum estrus in pregnant rats.

To test the hypothesis that the onset of maternal behavior is stimulated by estrogen, we examined the effects of medial preoptic area (MPOA) or ventromedial hypothalamus (VMH) implants of the antiestrogen 4-hydroxytamoxifen (OH-TAM) on pre- and postpartum maternal behavior and on postpartum estrus in rats. On day 20 of pregnancy, animals were implanted bilaterally with OH-TAM or cholesterol cannulae into MPOA or VMH. Unilateral cannulae of OH-TAM were also placed into MPOA. Females were tested with newborn pups for the onset of immediate retrieval, prepartum, at noon on day 21, at midnight of the day 21, and 1 day following parturition (which occurred on day 22). On the evening of parturition, implanted animals were tested with stimulus males for the occurrence of postpartum estrus. In order to examine the influence of estrogen on maternal behavior in the absence of parturitional experience, antiestrogen-implanted animals were delivered surgically (cesarean section) and were observed for the display of maternal behavior at various times after surgery. At noon of day 21, only a few animals in any group retrieved pups. However, 12 h later, females that received bilateral OH-TAM implants into MPOA remained nonresponsive, while over 80% animals in other groups retrieved and gathered pups. The antiestrogen did not disrupt the display of postpartum maternal behavior in those females that were allowed to undergo normal parturition, but it significantly reduced the number of cesarean-delivered animals showing maternal behavior. Bilateral implants of OH-TAM into VMH, but not into MPOA, effectively blocked postpartum estrus. The MPOA implants of OH-TAM resulted in a significant reduction in cytoplasmic estrogen receptor levels and an increase in nuclear estrogen receptor concentrations. The results of these experiments lend support to the current hypothesis that estrogen acts most effectively in the MPOA to stimulate maternal behavior and in the VMH to facilitate sexual receptivity.

Animals↗
PubMedDate not supplied

Reciprocal effects of tamoxifen on hormonal cytology in postmenopausal women.

OBJECTIVE: To evaluate the estrogenic effect of tamoxifen (TAM) therapy in postmenopausal women. STUDY DESIGN: The subjects were 26 postmenopausal women. The maturation index (MI), maturation value (MV) and karyopyknotic index (KPI) were evaluated based on hormonal cytology. Endometrial cytologic examinations and transvaginal ultrasonography were also performed. RESULTS: Of the 26 patients, 16 had low estrogenic activity from the viewpoint of hormonal cytology before TAM administration. During administration, their mean MV rose significantly, from 25.8 +/- 17.7 to 68.8 +/- 13.2, (mean +/- SD) and their mean KPI rose from 9.0 +/- 8.3 to 47.1 +/- 23.1. In contrast, among the 10 patients with high estrogenic activity, mean MV and KPI decreased from 62.9 +/- 8.4 and 27.2 +/- 16.9 to 58.4 +/- 7.7 and 17.7 +/- 16.1, respectively, with TAM administration. Mean endometrial thickness increased more significantly with TAM administration in the low estrogenic activity group than in the high estrogenic activity group. CONCLUSION: TAM had a reciprocal effect; no additional estrogenic effect was seen in patients with high estrogenic activity. Conversely, an estrogenic effect was seen in those with low estrogenic activity. An individualized gynecologic evaluation based on hormonal cytology is useful in selecting patients who will be more susceptible to TAM-induced endometrial abnormality.

Aged↗
PubMed1990

Sequential alternate administration of tamoxifen and medroxyprogesterone acetate in advanced breast cancer: clinical-biological randomized study.

From January 1985 to September 1988, 60 women with advanced breast cancer were randomized in two arms to receive: A) tamoxifen (TAM) (20 mg/die) until progression or B) TAM (20 mg/die for 14 days) then medroxyprogesterone acetate (MPA) (1500 mg/die p.o. for 14 days) followed by 7 days of wash-out before repeating the TAM/MPA treatment. All patients were post-menopausal, previously untreated with hormone therapy, and with tumor receptor status determined immediately before randomization; all had objectively evaluable lesions. In order to verify hormone receptor variations due to the antiestrogen, when possible a second biopsy was performed after the initial 14 day cycle of TAM. Thirty-one and 29 patients were included respectively in arms A and B. Objective regression (CR + PR) was observed in 58% of group A and 75% of group B, with CR in 11% and 23%, respectively. Differences were not statistically significant. Median time to progression was 12 months for group A and 9 for group B. Overall survival has not yet been reached in group A while it was 34 months for patients of group B. Metrorrhagia was observed in two cases of group A and in 6 of group B, and thrombophlebitis in 1 and 3 cases, respectively. The second biopsy confirmed a clear increase of PgR content in 8/11 cases (75%). Plasma level variations of TAM, N-desmethyl TAM and MPA were checked at various intervals on 3 patients of group B, and confirmed that our schedule is able to produce a drug wash-out period for tumor cells. In conclusion, our study demonstrated that while the manipulation of hormone receptors seems possible, results indicating better overall survival and time to progression were not obtained with alternate sequential TAM-MPA therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation).

To identify the molecular basis underlying the functions of tumor-associated macrophages (TAMs), we characterized the gene expression profile of TAMs isolated from a murine fibrosarcoma in comparison with peritoneal macrophages (PECs) and myeloid suppressor cells (MSCs), using a cDNA microarray technology. Among the differentially expressed genes, 15 genes relevant to inflammation and immunity were validated by real-time polymerase chain reaction (PCR) and protein production. Resting TAMs showed a characteristic gene expression pattern with higher expression of genes coding for the immunosuppressive cytokine IL-10, phagocytosis-related receptors/molecules (Msr2 and C1q), and inflammatory chemokines (CCL2 and CCL5) as expected, as well as, unexpectedly, IFN-inducible chemokines (CXCL9, CXCL10, CXCL16). Immunohistology confirmed and extended the in vitro analysis by showing that TAMs express M2-associated molecules (eg, IL-10 and MGL1), as well as CCL2, CCL5, CXCL9, CXCL10, and CXCL16, but no appreciable NOS2. Lipopolysaccharide (LPS)-mediated activation of TAMs resulted in defective expression of several proinflammatory cytokines (eg, IL-1beta, IL-6, TNF-alpha) and chemokines (eg, CCL3), as opposed to a strong up-regulation of immunosuppressive cytokines (IL-10, TGFbeta) and IFN-inducible chemokines (CCL5, CXCL9, CXCL10, CXCL16). Thus, profiling of TAMs from a murine sarcoma revealed unexpected expression of IFN-inducible chemokines, associated with an M2 phenotype (IL-10high, IL-12low), and divergent regulation of the NF-kappaB versus the IRF-3/STAT1 pathway.

Animals↗
PubMed1994

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group (GBSG) started a multicenter randomized clinical trial to compare the effectiveness of three versus six cycles of 500 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil (CMF) on day 1 and 8 starting perioperatively with or without tamoxifen (TAM) (3 x 10 mg/d for 2 years). The aim of the trial was to compare recurrence-free and overall survival between the different treatment modalities. PATIENTS AND METHODS: During 5 years, 41 institutions randomized 473 patients (3 x CMF: 145; 3 x CMF + TAM: 93; 6 x CMF 144; 6 x CMF + TAM: 91). Until March 31, 1992, median follow-up time was 56 months with 197 events for disease-free survival and 116 deaths observed. This provides a power of approximately 80% to detect a potential treatment difference corresponding to a relative risk (RR) of 0.67 for recurrence-free survival. Treatment modalities and various patient characteristics were evaluated by means of a multivariate Cox regression analysis. RESULTS: No significant difference in recurrence-free survival was observed with respect to hormonal therapy (RR = 0.75 TAM v no TAM; 95% confidence interval [CI], 0.54 to 1.04; P = .08) as well as duration of chemotherapy (RR = 0.90 of 6 x CMF v 3 x CMF; 95% CI, 0.67 to 1.19; P = .45). Similar results were obtained for overall survival. The multivariate analysis revealed a significant prognostic impact of the number of positive lymph nodes and the progesterone receptor level on recurrence-free survival. Compliance with chemotherapy within the range of 85% to 115% of the target dose was achieved in 94% and 78% of the patients randomized to 3 x CMF and 6 x CMF, respectively. Sufficient compliance with TAM was reported for 141 patients (93%). CONCLUSION: At this stage of follow-up, six courses of CMF are not superior to three courses with respect to recurrence-free survival.

Adult↗
PubMed1999

Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

Adult↗
PubMed1999

Epirubicin plus tamoxifen versus tamoxifen alone in node-positive postmenopausal patients with breast cancer: A randomized trial of the International Collaborative Cancer Group.

PURPOSE: To assess whether the addition of epirubicin (EPI) therapy to prolonged treatment with tamoxifen (TAM) improves relapse-free and overall survival in postmenopausal women with node-positive primary breast cancer. PATIENTS AND METHODS: Six hundred four patients entered onto a randomized clinical trial were allocated to receive TAM 20 mg/d for 4 years or TAM 20 mg/d for 4 years plus EPI 50 mg/m(2) intravenously on days 1 and 8 every 4 weeks for six cycles. Analysis was performed according to allocated treatment, with all randomized patients included (intention to treat), irrespective of eligibility status. RESULTS: After a median follow-up period of 5.7 years, an improvement in relapse-free survival (RFS) was observed for the TAM and EPI-treated patients, compared with those who received TAM alone. The unadjusted hazard ratio was 0.72 (95% confidence interval, 0.54 to 0.96), with a corresponding reduction in the odds of recurrence of 27.9% (SD, 12. 3), which was statistically significant (P =.023). Adjustment for prognostic and/or predictive factors did not materially affect the hazard ratio. No difference was observed in terms of overall survival (reduction in odds of death, 11.9% [SD, 16.3]; P =.46). Combined chemohormonal treatment was associated with a higher incidence of acute side effects but without a clear increase in long-term cardiotoxicity. Twelve nonbreast second malignancies, including five hematologic malignancies (two of which were cases of acute myelogenous leukemia), were observed. CONCLUSION: The data show that combined chemohormonal treatment reduces the risk of relapse in postmenopausal patients with node-positive breast cancer. No evidence was found, however, for an improvement in overall survival. The size of benefit observed for both outcomes was consistent with that reported in the Early Breast Cancer Trialists' Collaborative Group overview. The trial presented here, however, provides the first report of an improvement in RFS associated with the provision of a single cytotoxic drug in addition to prolonged TAM.

Adult↗
PubMed2001

Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.

Age Factors↗
PubMed1986

Effects of the antiestrogens tamoxifen and clomiphene on bone resorption in vitro.

The in vitro effect of the nonsteroidal antiestrogens tamoxifen (TAM) and clomiphene (CLO) on bone resorption was investigated. TAM (100 microM) and CLO (100 microM) completely blocked PTH (2 nM)-induced resorption; 10 microM TAM was ineffective in blocking resorption, while 40-50 microM partially inhibited the response. TAM (100 microM) also completely blocked prostaglandin E2 (30 nM)- and 1,25-dihydroxy vitamin D3 (0.5 nM)-induced bone resorption. A 16-h pretreatment with TAM blocked subsequent stimulation of resorption by PTH, whereas 3.5- or 7-h pretreatment with antiestrogen was ineffective in blocking the response. Both protein and DNA syntheses were inhibited by continuous treatment (48 h) with the antiestrogens. When antiestrogen-pretreated (16 h) bones were transferred to fresh medium not containing antiestrogen, protein and DNA syntheses recovered to approximately half the control (nonantiestrogen-treated) values within 48 h. Bone resorption, however, was still completely inhibited even though macromolecular synthesis had substantially recovered. Thus, mechanisms other than macromolecular synthesis inhibition could be involved in the inhibition of bone resorption by the nonsteroidal antiestrogens TAM and CLO.

Animals↗
PubMed1988

Differential induction of progestin-binding sites in uterine cell types by estrogen and antiestrogen.

Effects of antiestrogen on progestin binding in uterine cell types were determined and compared to those of estrogen. Effects on uterine morphology were also studied. Immature rats were treated with four daily sc injections of 100 micrograms hydroxytamoxifen [TAM(OH)], 5 micrograms estradiol (E2), or oil. On day 5 the rats were injected iv with 1 microgram of the synthetic progestin [3H]Org 2058, and 1 h later uteri were excised, weighed, and processed for thaw-mount autoradiography. Treatment with TAM(OH) or E2 resulted in uterine weight gain, which was greater in animals treated with E2. E2 treatment resulted in cellular hypertrophy in all tissue compartments, especially in the luminal epithelium and myometrium, but TAM(OH) treatment resulted in hypertrophy of only the luminal epithelium. Treatment with TAM(OH) or E2 changed the pattern and intensity of nuclear binding of [3H]Org 2058 from that in oil-treated controls. E2 increased progestin binding in stroma and myometrium and decreased it in luminal epithelium. TAM(OH), similarly, decreased progestin binding in the luminal epithelium and increased it, albeit less than E2, in the myometrium, but left it unchanged in the stroma. The results indicate that E2 and TAM(OH) differentially effect progestin binding among the uterine tissue compartments.

Animals↗
PubMed1991

Cell cycle phase dependence of estrogen and epidermal growth factor (EGF) receptor expression in MCF-7 cells: implications in antiestrogen and EGF cell responsiveness.

In this report the effect of epidermal growth factor (EGF) and the antiestrogen hydroxytamoxifen (OH-TAM) on the cell cycle of the breast cancer cell line MCF-7 was investigated as a function of the presence of their respective receptors. For this study synchronized cells were obtained by cell incubation in the presence of 2 mM thymidine for 24 h at 37 C. The treatment led to a partial synchronization, since at the end of thymidine treatment, 80% of cells were accumulated in the G1 phase. The removal of thymidine allowed the cells to progress through the cell cycle, since between 6-9 h after the arrest of the treatment, about 50% of cells were found in the S phase. By 9-12 h, most of the cells entered the G2 phase, and by 24 h, the cells returned to the G1 phase. When MCF-7 cells were incubated in the presence of OH-TAM for various periods of time before thymidine exposure, the progression of the cells through the cell cycle was dramatically inhibited. Also, a short term antiestrogen treatment (2 h) before or immediately after the addition of thymidine led to an accumulation of MCF-7 cells in the G1 phase. However, when the cells were treated for 2 h with OH-TAM 22 h after thymidine addition or shortly after its removal from the cell culture, no effect of the antiestrogen on the cell cycle could be observed. In parallel, the effect of thymidine on the level of estrogen receptor was studied. Although low affinity estrogen-binding sites were maintained, high affinity ER were found to be dramatically reduced during the thymidine treatment. The comparison between the effect of OH-TAM on the cell cycle and the expression of ER revealed that the antiestrogen OH-TAM was effective only in the presence of ER. EGF was found to have no effect on the cell cycle of thymidine-synchronized cells, although it did partially reverse the G1 phase block induced by OH-TAM when added simultaneously to cell culture 24 h before thymidine exposure. The parallel analysis of EGF receptor level demonstrated that thymidine treatment also reduced EGF receptors that were found to reappear after the synchronization, during the S and G2 phases of the cell cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding Sites↗
PubMed1983

Inhibitory action of bromocriptine and tamoxifen on the growth of human pituitary tumors in soft agar.

Human pituitary tumors were studied in vitro using the clonogenic stem cell assay. Mechanical dispersion was used to prepare single cell suspensions for plating. Colony formation occurred in 21 of 24 tumors plated. Bromocriptine (Brc; 10 nM) added to the medium resulted in a significant decrease in the number of colonies formed in 5 of 10 prolactinomas and in 1 tumor secreting both PRL and GH. However, PRL secretion was decreased in 8 of 9 tumors tested. Brc had no effect on either colony formation or hormone secretion in other tumors secreting GH (n = 2), ACTH (n = 2), or FSH (n = 1) or in nonsecreting tumors (n = 4). Tamoxifen (Tam; 10(-7) M) inhibited colony formation in 6 of 10 prolactinomas and in 1 tumor secreting GH and PRL. PRL secretion into the medium correlated with the changes in the number of colonies. Tam was not effective in any other tumor tested. In only 1 instance was there a synergistic action between Brc and Tam on inhibition of colony formation. Brc, but not Tam, caused a significant decrease in the size of the colonies formed from cells of PRL-secreting tumors. The least numbers of colonies per plate were found in 3 prolactinomas from patients treated preoperatively with Brc. We conclude that the soft agar clonogenic assay technique is a feasible method to study human pituitary tumors in vitro. Both Brc and Tam inhibited colony formation in this system in a significant proportion of tumors. The potential antiproliferative action of Tam in vivo needs to be studied in view of these results.

Adenoma↗
PubMed1995

The short term effects of tamoxifen on bone turnover in older women.

This study examined the effects of tamoxifen (TAM) on biochemical markers of bone turnover in healthy women, 20-30 yr past menopause. Ten women (mean age, 75 yr; range, 70-85 yr) were given TAM (20 mg/day) for 10 weeks. Serum and urine were collected twice at baseline, at weeks 9 and 10 of TAM treatment, and at weeks 9 and 10 post-TAM. Markers of bone formation were serum osteocalcin, total alkaline phosphatase, bone-specific alkaline phosphatase, and type I procollagen peptide. Markers of bone resorption were fasting urinary calcium, hydroxyproline, pyridinoline, and deoxypyridinoline, all corrected for urinary creatinine. Total cholesterol, triglycerides, and high density lipoproteins were measured; low density lipoprotein levels were calculated. Pyridinoline and deoxypyridinoline decreased during therapy by 23% and 25% and returned to baseline posttherapy (F = 37.01; P = 0.001), with no significant changes in urinary calcium and hydroxyproline. Markers of bone formation declined 17-36%, with a variable return toward baseline (F = 85.56; P < 0.001). Ionized calcium decreased 5% (P < 0.001) and PTH increased 21% (P = 0.05) during TAM treatment. Total cholesterol decreased 15% (P < 0.001), and calculated low density lipoprotein cholesterol decreased 22% (P < 0.001); levels of triglycerides and high density lipoprotein did not change significantly. We conclude that short term TAM treatment inhibits bone turnover in women over 70 yr of age.

Aged↗
PubMed1994

Antiestrogens increase protein tyrosine phosphatase activity in human breast cancer cells.

Growth of human breast cancer cells is controlled by multiple interacting factors that trigger different intracellular signaling pathways. The nonsteroidal antagonist 4-hydroxytamoxifen (OH-Tam), which acts as an antiestrogen, is also able to inhibit the mitogenic activity of epidermal growth factor (EGF) on hormone-responsive MCF7 cells. To further characterize the mechanism of this antigrowth factor activity, which is accompanied by an increase of high-affinity EGF binding and a drastic decrease in EGF receptor autophosphorylation, we studied the effect of OH-Tam on protein tyrosine phosphatase (PTPase) activity with specific in vitro assays using two different substrates. OH-Tam increased membrane PTPase activity in a time- and dose-dependent fashion whereas cytoplasmic enzyme activity remained unchanged. The increase in PTPase activity was mediated by the estrogen receptor (ER) since it was restricted to ER-positive cells, and the optimal OH-Tam concentration (ED50 = 1 nM) was correlated with the ligand affinity for ER. The increase in enzyme activity was selectively obtained with nuclear receptor ligands (OH-Tam, ICI 164,384) that inhibited growth factor-induced proliferation, whereas other inhibitors of estrogenic responses such as synthetic progestins and antiprogestins had no effect. The time course of stimulation (maximal stimulation at day 4) was concomitant to the loss of EGF mitogenic response. Moreover, addition of a specific PTPase inhibitor (5 microM sodium orthovanadate) to intact cells in culture prevented OH-Tam inhibition of cell proliferation, suggesting that these two events are closely associated.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog.

We previously identified a codon 351 (Asp-->Tyr) mutant estrogen receptor (ER) in a tamoxifen-stimulated human breast tumor line. To examine its biological activity, we have constructed cell lines from the ER-negative human breast cancer cell line MDA-MB-231 that stably express either the wild type (S30) or mutant ER (BC-2). ER expression was confirmed by Western blot, ligand-binding studies, and ER-enzyme immunoassay. The growth characteristics of the S30 and BC-2 cell lines were compared when treated with estradiol, fixed-ring 4-hydroxytamoxifen [(fr) 4-OH TAM], or ICI 182,780. (fr) 4-OH TAM is a stable, high affinity tamoxifen analog. Many investigators have recognized that growth of ER-negative cell lines stably transfected with ER is inhibited by estradiol. Similarly, both S30 and BC-2 cell lines are inhibited by estradiol in a concentration-dependent manner. (fr) 4-OH TAM has no effect on S30 proliferation but inhibits the growth of BC-2 cells. The pure antiestrogen ICI 182,780 can block the growth-inhibitory effect of estradiol in both cell lines and the growth-inhibitory effect of (fr) 4-OH TAM in the BC-2 cells. In transient transfection analyses using a luciferase reporter plasmid containing two copies of the Xenopus vitellogenin A2 estrogen response element, estradiol stimulated luciferase transcription through both the wild type and mutant estrogen receptors, while (fr) 4-OH TAM stimulated transcription to a greater extent through the mutant receptor. These results demonstrate that the estrogenicity of (fr) 4-OH TAM is increased by binding to the codon 351 mutant ER, and that ER activation and growth inhibition are associated.

Amino Acid Sequence↗