transforming-growth-factor-alpha and Uterine-Neoplasms

Topics: Animals; Breast Neoplasms; Drug Resistance, Neoplasm; Estrogen Antagonists; Estrogens; Female; Humans; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Tamoxifen; Transforming Growth Factor alpha; Uterine Neoplasms

We have determined the gene expression profile induced by 17 alpha-ethynyl estradiol (EE) in Ishikawa cells, a human uterine-derived estrogen-sensitive cell line, at various doses (1 pM, 100 pM, 10 nM, and 1 microM) and time points (8, 24, and 48 h). The transcript profiles were compared between treatment groups and controls (vehicle-treated) using high-density oligonucleotide arrays to determine the expression level of approximately 38,500 human genes. By trend analysis, we determined that the expression of 2560 genes was modified by exposure to EE in a dose- and time-dependent manner (p

Topics: Animals; Cell Line; Databases, Genetic; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Gene Expression; Gene Expression Profiling; Genes; Humans; Oligonucleotide Array Sequence Analysis; Rats; RNA, Messenger; Time Factors; Transforming Growth Factor alpha; Uterine Neoplasms; Uterus

The loss of function of the tumor suppressor gene TSC2 and its protein product tuberin promotes the development of benign lesions by stimulating cell growth, although the role of tuberin in regulating cell migration and metastasis has not been characterized. In addition, the role of phosphatidylinositol 3-kinase (PI 3-kinase), an important signaling event regulating cell migration, in modulating tuberin-deficient cell motility remains unknown. Using a tuberin-deficient rat smooth muscle cell line, ELT3, we demonstrate that platelet-derived growth factor (PDGF) stimulates cell migration by 3.2-fold, whereas vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-alpha, and basic fibroblast growth factor (bFGF) increase migration by 2.1-, 2.1-, and 2.6-fold, respectively. Basal and PDGF-induced migration in tuberin-deficient ELT3, ELT4, and ERC15 cells was not significantly different from that of tuberin-positive transformed rat kidney epithelial 2, airway smooth muscle, and pulmonary arterial vascular smooth muscle cells. Expression of tuberin in tuberin-deficient ELT3 cells also had little effect on cell migration. In parallel experiments, the role of PI 3-kinase activation in ELT3 cell migration was investigated. LY-294002, a PI 3-kinase inhibitor, decreased PDGF-induced migration in a concentration-dependent manner with an IC(50) of approximately 5 microM. LY-294002 also abrogated ELT3 cell migration stimulated by bFGF and TGF-alpha but not by VEGF and phorbol 12-myristate 13-acetate. Furthermore, transient expression of constitutively active PI 3-kinase (p110*) was sufficient to induce ELT3 cell migration. However, the migration induced by p110* was less than that induced by growth factors, suggesting other signaling pathways are also critically important in modulating growth factor-induced cell migration. These data suggest that PI 3-kinase is required for growth factor-induced cell migration and loss of tuberin appears to have little effect on cell migration.

Topics: Animals; Anticoagulants; Becaplermin; Cell Movement; Endothelial Growth Factors; Enzyme Activation; Female; Fibroblast Growth Factor 2; Gene Expression; Leiomyoma; Lung; Lymphokines; Muscle, Smooth; Phosphatidylinositol 3-Kinases; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Repressor Proteins; Transforming Growth Factor alpha; Tuberous Sclerosis Complex 2 Protein; Tumor Cells, Cultured; Tumor Suppressor Proteins; Uterine Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The role of growth factors in the development of murine uterine mesenchymal tumors is unknown. In this study, immunohistochemical expression of transforming growth factor alpha (TGF-alpha) and its receptor epidermal growth factor (EGF-R) was assessed in spontaneous uterine leiomyomas and leiomyosarcomas in B6C3F1 mice. Cell proliferation, which has been induced by some growth factors, was evaluated by immunohistochemical detection of an endogenous marker of cell proliferation, proliferating cell nuclear antigen (PCNA). PCNA labeling indices were determined and compared to the intensity and distribution of TGF-alpha staining in sequential sections of control myometrium or tumor tissue. Results showed uterine leiomyosarcomas had positive cytoplasmic staining for TGF-alpha; however, all uterine leiomyomas evaluated were negative. Positive EGF-R staining was also observed in the uterine leiomyosarcomas, but not in the leiomyomas. EGF-R immunoexpression was detected primarily within the cytoplasm of the leiomyosarcoma cells, with occasional nuclear immunoreactivity. Immunohistochemical staining for PCNA was more intense and there were increased numbers of positively staining nuclei in the leiomyosarcomas compared to samples of control myometrium or leiomyomas. The mean labeling index for the uterine leiomyosarcomas (7.40%) was significantly (p < 0.01) higher than that of leiomyomas (0.29%) and control uterine myometrium (0.13%). We conclude, that TGF-alpha and its receptor, EGF-R, are expressed more intensely in uterine leiomyosarcomas, compared to leiomyomas in B6C3F1 mice. Immunoexpression of TGF-alpha may be an important biomarker of malignancy in uterine smooth muscle tumors in mice. Futhermore, TGF-alpha may play a critical role in increased proliferation of uterine smooth muscle tumor cells as suggested by increased immunolocalization of PCNA in rodent leiomyosarcomas expressing TGF-alpha, although other factors regulating cell replication can not be ruled out.

Topics: Animals; ErbB Receptors; Female; Immunohistochemistry; Leiomyoma; Leiomyosarcoma; Mice; Proliferating Cell Nuclear Antigen; Transforming Growth Factor alpha; Uterine Neoplasms

Immunolocalization of transforming growth factor alpha (TGF-Alpha), epidermal growth factor (EGF), insulinlike growth factor (IGF)-I, vascular endothelial growth factor (VEGF(165,189,121)), basic fibroblast growth factor (FGF)-2, EGF receptor (R), IGF-IRbeta, and FGFR-1 was studied in uterine leiomyomas and matched myometrial samples taken from seven women (42-47 years of age) in the proliferative phase of the menstrual cycle. Immunolocalization of growth factor peptides was accomplished with either monoclonal or polyclonal antibodies to the amino or carboxy terminus of growth factor peptides or their respective receptors, or against full-length recombinant growth factor. All reactions were conducted using the avidin-biotin complex method. Immunolocalization of TGF-alpha, EGF, EGF-R, IGF-I, IGF-IRbeta, FGF-2, FGFR-1, and VEGF was observed in the cytoplasm of smooth-muscle cells of leiomyomas and matched myometrium. The cytoplasm of vascular smooth-muscle cells expressed TGF-alpha, EGF, EGF-R, IGF-I, IGF-IRbeta, FGF-2, FGFR-1, and VEGF, whereas the vascular endothelium was positive for TGF-alpha, EGF, EGF-R, FGF-2, and FGFR-1 in both leiomyomas and matched myometria. Fibroblasts within the fibrous component of some leiomyomas were positive for IGF-I and FGF-2 and minimally positive for FGFR-1. In addition, the extracellular matrix of leiomyomas showed focal localization of FGF-2 and IGF-I in some tumors. When scores of intensity and percent positive staining were compared, IGF-IRbeta was significantly increased in the leiomyomas compared to matched myometria, whereas EGF was significantly decreased in the uterine leiomyomas compared to matched myometria. In summary, these data revealed growth factors to be expressed differentially in smooth muscle, vascular and fibroblastic cell types of leiomyomas and matched myometria. Specifically, IGF-IRbeta was significantly increased in leiomyomas; although a similar increase was seen with IGF-I peptide, statistical significance was not achieved. The EGF peptide was significantly decreased in the leiomyomas compared to matched myometrium. These data suggest that IGF-IRbeta and IGF-I peptide may be one of several growth factor/receptor pathways important in uterine leiomyoma growth during the proliferative phase of the menstrual cycle. In addition, decreased EGF may be secondary to the predominant estrogenic milieu present at time of sampling, as it has been proposed that progesterone, and not estrogen, may regulate E

Topics: Adult; Case-Control Studies; Endothelial Growth Factors; Epidermal Growth Factor; ErbB Receptors; Female; Fibroblast Growth Factor 2; Growth Substances; Humans; Immunohistochemistry; Leiomyoma; Lymphokines; Menstrual Cycle; Middle Aged; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 1; Receptor, IGF Type 2; Receptors, Fibroblast Growth Factor; Receptors, Growth Factor; Somatomedins; Transforming Growth Factor alpha; Uterine Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To analyse prognostic factors in complete hydatidiform moles using multiple logistic regression analysis.. Evaluation of host and tumour related parameters including (a) gestational age, patient age, parity, molar phenotype, grade of proliferation of the tumour and cytological atypia, (b) expression of beta-HCG, EGF, EGFR, TGF-alpha, TGF-beta, IL1-alpha, IL1-beta by immunohistochemistry, (c) serial monitoring of serum beta-HCG levels by ELISA, and (d) lectin binding using jack fruit lectin histochemistry as indices for persisting trophoblastic disease (PTD).. Serum beta-HCG levels at 4 weeks, cellular atypia, lectin binding, expression of TGF-alpha and IL1-beta showed highly significant correlation with persistence of the tumour (P<0.001). The sensitivity and specificity at 4 weeks in combination with cytological atypia to identify spontaneously regressing lesions was 100% and those requiring chemotherapeutic intervention was 80%.. The concentration of serum beta-HCG 4 weeks post evacuation(<300 mIU/ml) combined with cytological abnormalities could identify nearly 100% of the spontaneously regressing lesions (low risk) and 80% of those needing chemotherapeutic intervention (high risk), thereby suggesting that patients who have a serum beta-HCG at 4 weeks of evacuation <300 mIU/ml with no cytological atypia of the trophoblasts need only be followed up at long intervals, while those having a serum beta-HCG at 4 weeks of evacuation >300 mIU/ml accompanied with cytological atypia of the trophoblasts should be closely followed up.

Topics: Chorionic Gonadotropin, beta Subunit, Human; Female; Humans; Hydatidiform Mole; Interleukin-1; Lectins; Logistic Models; Multivariate Analysis; Plant Lectins; Pregnancy; Prognosis; Sensitivity and Specificity; Transforming Growth Factor alpha; Uterine Neoplasms

We studied the estrogen-dependent expression of epidermal growth factor (EGF), transforming growth factor (TGF) alpha, and EGF receptor gene transcripts in human fallopian tubes in vivo and in vitro. Competitive polymerase chain reaction (PCR) was performed on the fallopian tube RNA samples from the postmenopausal women with or without estrogen replacement. Amounts of EGF, TGF alpha, and EGF receptors gene transcripts in the estrogen-treated group (n = 3) were significantly (P < 0.01) more than those in the untreated group (n = 3). Competitive PCR also showed that EGF, TGF alpha, and EGF receptor gene transcripts level in tubal cells were increased by estrogen in vitro: messenger RNA levels of these factors were significantly (P < 0.01, n = 3) increased in cells incubated with 10(-8) M estrogen compared with those in cells without estrogen treatment. We studied whether EGF and/or TGF alpha is involved in the estrogen-induced tubal cell growth in vitro. Estrogen enhanced the [3H]-thymidine incorporation into the cell in dose- and time-dependent manners in culture: estrogen treatment for more than 12 h significantly (P < 0.05) enhanced the [3H]-thymidine incorporation into the cell at 10(-8) M. The estrogen-induced cell growth was observed in association with the increase in EGF, TGF alpha, and EGF receptor messenger RNA levels by estrogen. If the EGF and/or TGF alpha is involved in the cell growth, then the estrogen-induced cell growth should be suppressed by blocking the action of EGF and/or TGF alpha. Therefore, we examined the effects of neutralizing monoclonal antibodies against EGF, TGF alpha, and EGF receptors. Anti-EGF antibody significantly reduced the estrogen-induced increase in [3H]-thymidine incorporation, whereas anti-TGF alpha antibody failed to show the effect. Anti-EGF receptor antibody showed a significant suppressive effect on the estrogen-induced increase in [3H]-thymidine incorporation. Moreover, the growth inhibitory effect by 1 microgram/ml anti-EGF was restored by 10(-8) M EGF but not by TGF alpha even at 10(-6) M. All these data suggest that estrogen induces EGF and TGF alpha/EGF receptors in the human fallopian tube and that EGF but not TGF alpha may be involved in the estrogen-induced human tubal cell growth in vitro.

Topics: Antibodies, Monoclonal; Base Sequence; Catechols; Cells, Cultured; DNA; DNA Primers; Epidermal Growth Factor; Epithelium; ErbB Receptors; Estrogens, Conjugated (USP); Fallopian Tubes; Female; Gene Expression; Growth Inhibitors; Humans; Hysterectomy; Leiomyoma; Middle Aged; Molecular Sequence Data; Nitriles; Polymerase Chain Reaction; Postmenopause; Thymidine; Transforming Growth Factor alpha; Tyrphostins; Uterine Neoplasms

Trophoblastic cells abundantly express epidermal growth factor (EGF) receptors, which, when activated by EGF or transforming growth factor-alpha, can influence cellular growth and metabolism. Various lymphocyte and macrophage cytokines have been found to influence the proliferation of human choriocarcinoma (CCA) cells in vitro. In the current study we investigated the possibility that certain cytokine effects are mediated by changes in EGF receptor expression. JEG-3 human CCA cells were incubated with varying concentrations of interleukin 1-alpha (IL-1 alpha), interleukin 1-beta (IL-1 beta), interleukin 2, gamma-interferon, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha (TNF), and the expression of EGF receptor was measured by radioimmunoassay using a murine monoclonal antibody with specificity for the EGF receptor. Proliferative or growth suppressive effects of the cytokines were assessed by quantitative analysis of the DNA in the cell culture wells. Macrophage-derived cytokines IL-1 alpha, IL-1 beta and TNF significantly suppressed cell growth; this was associated with a significant increase in EGF receptor expression. The other cytokines had no significant effect on either EGF receptor expression or cell growth. We also studied the expression of EGF mRNA in JEG-3, Jar and BeWo CCA cell lines. By reverse transcription followed by polymerase chain reaction, low levels of EGF mRNA were detected in all three cell lines. Therefore, EGF may be synthesized by JEG-3, Jar and BeWo CCA cell lines to participate in an autocrine growth pathway. Our findings support the concept that cytokines may act as paracrine mediators of autocrine processes involved in CCA cell growth regulation by modulating growth factor receptor expression.

Topics: Blotting, Northern; Cell Count; Cell Division; Choriocarcinoma; Cytokines; DNA, Neoplasm; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Polymerase Chain Reaction; Radioimmunoassay; RNA, Messenger; RNA, Neoplasm; Transcription, Genetic; Transforming Growth Factor alpha; Tumor Cells, Cultured; Uterine Neoplasms

Epidermal growth factor (EGF) elicits estrogen receptor (ER)-dependent physiological sequelae and estrogen-like biochemical effects on the ER in the mouse uterus. These in vivo observations indicate that EGF may elicit some of its actions by activation of the ER. The effect of peptide growth factors on activation of a consensus estrogen-responsive element was assessed in a strain of Ishikawa human endometrial adenocarcinoma cells with negligible levels of ERs, as determined by Western blot and [3H]estradiol binding, and in BG-1 human ovarian adenocarcinoma cells, which contain abundant ERs. EGF and transforming growth factor-alpha induced transcriptional activation of a consensus ERE in an ER-dependent manner in both cell types. Transcriptional activation by the growth factors was inhibited by ICI 164,384, an ER receptor antagonist, and neutralizing antibodies to the EGF receptor. Immunodetection of the ER in BG-1 cells demonstrated that receptor levels were not induced by transforming growth factor-alpha vs. untreated cells. ER deletion mutants containing amino acids 1-339 and 121-599 were transfected into Ishikawa cells. The 1-339 mutant was more active in inducing transcription after EGF treatment than the 121-599 mutant. Estrogen only stimulated transcription in the presence of the 121-599 mutant, while 1-339 was inactive. Interestingly, synergism between a physiological dose of estrogen and peptide growth factors was observed. The presence of cross-talk between EGF receptor and ER signaling pathways suggests that interactions between growth factors and steroid receptors may modulate hormonal activity influencing normal and aberrant function in mammalian cells.

Topics: Adenocarcinoma; Animals; Base Sequence; Epidermal Growth Factor; Estradiol; Estrogen Antagonists; Female; Gene Expression Regulation; Humans; Mice; Molecular Sequence Data; Ovarian Neoplasms; Polyunsaturated Alkamides; Promoter Regions, Genetic; Receptors, Estrogen; Recombinant Fusion Proteins; Recombinant Proteins; Regulatory Sequences, Nucleic Acid; Signal Transduction; Simian virus 40; Transcription, Genetic; Transforming Growth Factor alpha; Tumor Cells, Cultured; Uterine Neoplasms; Vitellogenins

Sex steroid hormone dependent cell proliferation and inducing growth factors of endometrial carcinoma cells were investigated using in vitro culture systems. The cell proliferation of Ishikawa cells derived from well-differentiated endometrial adenocarcinoma which possess both estrogen and progesterone receptors were stimulated by either estradiol added to culture media or EGF and TGF-alpha acting through EGF receptors. These stimulatory effects of TGF-alpha were antagonized by the anti TGF-alpha and EGF-receptor antibodies. The cell proliferations of other endometrial cancer cells were also inhibited by those antibodies. All endometrial cancer cells secrete TGF-alpha into their culture media measured by TGF-alpha ELISA methods. The expression of TGF-alpha mRNA and secretion of TGF-alpha of Ishikawa cells were induced by estradiol but not of hormone independent HEC-50 cells. Thus suggest that estradiol dependent growth factor should be TGF-alpha in human endometrial carcinoma cells.

Topics: Carcinoma, Endometrioid; Cell Division; Epidermal Growth Factor; ErbB Receptors; Estradiol; Female; Humans; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Receptors, Progesterone; RNA, Messenger; Transforming Growth Factor alpha; Tumor Cells, Cultured; Uterine Neoplasms

Basement membranes (BM) are elements of the extracellular matrix that are essential for growth and differentiation of tissues. Several collagenolytic enzymes of tumor cells are involved in degradation of the extracellular matrix; growth and inhibitor factors [e.g. Epidermal Growth Factor (EGF), Transforming Growth Factors alpha and beta (TGF-alpha, beta)] seem to be involved in the extracellular matrix formation and degradation. To establish a possible association between the presence of collagenase (C), urokinase-type plasminogen activator (uPA) and the neoplastic growth of the endometrium, 44 endometrial specimens (14 proliferative, 11 secretive, 7 adenomatous hyperplasia, 12 adenocarcinoma) were studied using immunohistochemistry with antisera for C, uPA, EGF receptors and TGF-alpha. Immunostaining for collagenase revealed a positive reaction in moderately differentiated adeno-carcinoma without staining the normal and hyperplastic endometrium. A progressive increase in uPA immunostaining was observed in proliferative and neoplastic endometrium. TGF-alpha and its receptor (EGFr) were stained in proliferative and more clearly in hyperplastic and carcinomatous endometrium. In conclusion, BM play an important role in proliferation and differentiation of human endometrium; their degradation influences estrogen transportation from blood to the stroma. Endometrial BM degradation is associated with the presence of collagenolytic enzymes and growth factors.

Topics: Adult; Basement Membrane; Endometrial Hyperplasia; Endometrium; ErbB Receptors; Female; Fibrinolytic Agents; Humans; Microbial Collagenase; Middle Aged; Peptide Hydrolases; Plasminogen Activators; Transforming Growth Factor alpha; Urokinase-Type Plasminogen Activator; Uterine Neoplasms

Endometriosis has been shown to be associated with increased number and activity of peritoneal macrophages. The peritoneal macrophage-conditioned media from 33 women with or without endometriosis were studied for their effects on an endometrial carcinoma cell line, ECC-1. The media from six of six stage III/IV cases demonstrated a mitogenic effect, which was blocked by an antibody to epidermal growth factor receptor. However, the conditioned media from seven of nine stage I/II cases and 14 of 18 normal women did not show a mitogenic effect. The difference between stage III/IV and the other two groups was significant (p less than 0.01). The incorporation of tritium-thymidine was three times higher with the media from stage III/IV cases, as compared with that of controls. When purified cytokines were tested in the tritium-thymidine uptake assay, only epidermal growth factor-transforming growth factor-alpha was mitogenic on ECC-1, whereas tumor necrosis factor, interleukin-1, and platelet-derived growth factor had no effect. Thus peritoneal macrophages in patients with endometriosis may play an important role in the progression of endometriosis, and the noted effects could be mediated by epidermal growth factor or a related growth factor.

Topics: Cell Division; Culture Media; Endometriosis; Female; Humans; Interleukin-1; Macrophages; Neoplasm Staging; Peritoneal Cavity; Platelet-Derived Growth Factor; Transforming Growth Factor alpha; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Uterine Neoplasms

In an attempt to understand the antiproliferative effects of progestins in endometrial cancer, we have examined the effects of the potent progestin, medroxyprogesterone acetate (MPA), on the cell proliferation and the expression of transforming growth factor (TGF) alpha and beta genes in human endometrial adenocarcinoma cell lines. The two cell lines used were Ishikawa, var 1, and HEC-50. In addition, the effects of exogenous TGF-alpha and anti-epidermal growth factor (EGF) receptor monoclonal antibody on cell proliferation were determined. Incubation of both cell lines with MPA resulted in a time- and dose-dependent inhibition of cell proliferation. Half-maximal growth inhibition was observed at 0.6 nM. In Ishikawa cells, the relative abundance of TGF-alpha was significantly reduced by MPA. A significant decrease in TGF-alpha mRNA was apparent 6 h after exposure to MPA and a further decrease was seen 12-24 h after addition of the progestin. The concentration of TGF-alpha immunoreactivity in conditioned medium of MPA-treated cells was also significantly reduced compared to control cultures. MPA had no effect on TGF-alpha expression by HEC-50 cells. EGF mRNA was not detected by Northern blot analysis in either cell type. MPA had no significant effect on EGF receptor mRNA abundance but resulted in a small increase in EGF receptor number in Ishikawa cells. Anti-EGF receptor monoclonal antibody (0.6-6 nM) inhibited Ishikawa cell growth but had no effect on HEC-50 cell proliferation. Exogenous TGF-alpha stimulated proliferation of both cell lines, but Ishikawa cells were significantly more sensitive to exogenous TGF-alpha than HEC-50 cells. Furthermore, TGF-alpha could reverse the growth inhibitory effects of MPA on Ishikawa cells. A decrease in TGF-beta mRNA abundance was also observed in MPA-treated Ishikawa and HEC-50 cells. This effect was of small magnitude, variable, and only observed after prolonged exposure to MPA. These observations are consistent with the hypothesis that the antiproliferative effects of progestins on Ishikawa cells are mediated by decreased expression and autocrine action of TGF-alpha. Since similar growth inhibition is also seen in the HEC-50 cells in which progestins have no effect on TGF-alpha expression, additional mechanisms are likely to be involved in the antiproliferative effects of progestins in human endometrial cancer.

Topics: Antineoplastic Agents; Female; Gene Expression Regulation, Neoplastic; Humans; Medroxyprogesterone; Medroxyprogesterone Acetate; RNA, Messenger; RNA, Neoplasm; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tumor Cells, Cultured; Uterine Neoplasms

Progesterone (P) and progestins play an important role in the control of endometrial growth. We have investigated P and progestin effects on endometrial estrogen extraction, on basement membrane (BM) synthesis and on the presence of the epidermal growth factor receptor (EGFr) in normal and pathologic endometrium. E2 uptake, evaluated in human isolated perfused uteri is significantly decreased by P. BMs investigated using immunohistochemistry, with antisera to collagen IV and laminin, were found around stromal cells only in the luteal phase or during P or progestin administration. Glandular BM, discontinuous in hyperplastic and carcinomatous endometria, were restored to integrity only in typical hyperplasia after therapy with progestin. Endometrial EGFr is modified by P: revelation of this antigen is increased in proliferative phase and decreased in secretory phase. Similarly this molecule was present in hyperplastic and carcinomatous endometria. Only in benign hyperplasia did we observe no staining for the same antigen after progestinic therapy. These data suggest that P or progestins may also have an indirect influence through mechanisms such as estrogen uptake and tissue factor activity with important differences between normal and pathologic endometrium.

Topics: Adult; Cell Membrane; Cell Transformation, Neoplastic; Collagen; Endometrial Hyperplasia; Endometrium; ErbB Receptors; Female; Humans; Immunohistochemistry; Laminin; Middle Aged; Neoplasm Invasiveness; Progesterone; Progestins; Transforming Growth Factor alpha; Uterine Neoplasms