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S S Bacus

Publications and source records attributed to S S Bacus.

35 records · Page 2Linked to original sources
PubMed1994

Medullary carcinoma is associated with expression of intercellular adhesion molecule-1. Implication to its morphology and its clinical behavior.

The histological hallmarks for the diagnosis of medullary breast cancer are circumscription, syncytial architecture, diffuse inflammatory infiltrate, and highly atypical nuclei. The biological and prognostic implication is a lower propensity to metastasize. We studied 19 medullary carcinomas for expression of the intercellular adhesion molecule-1 and lymphocyte-function-associated antigen-1, Neu differentiation factor, tumor necrosis factor-alpha, and the expression of HER-2/neu, HER-4, and HER-3 receptors. Our study revealed that all of the 19 medullary carcinomas expressed the intercellular adhesion molecule-1 and lymphocyte function associated antigen. Eighteen of 19 cancers expressed Neu differentiation factor and tumor necrosis factor-alpha. All medullary cancers expressed the HER-2/neu receptor, however, in the majority of the cases, the staining was confined to the cytoplasm. Only 4 of 12 cancers expressed HER-4 and none of the eight medullary cancers tested expressed HER-3. By comparison, in a control group of infiltrating ductal carcinomas, expression of intercellular adhesion molecule-1, lymphocyte function associated antigen-1, and Neu differentiation factor was positive in about 25 to 30% of the cases, HER-4 was expressed in 75% and HER-3 in 95% of the cases. Taken together, our observations suggest that the expression of intercellular adhesion molecule-1, lymphocyte function associated antigen, Neu differentiation factor, and tumor necrosis factor-alpha as factors that may affect the special morphology and the biological behavior that characterizes medullary carcinomas.

Breast Neoplasms↗
PubMed1993

Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors.

Neu differentiation factor (NDF, also called heregulin) is a 44-kilodalton glycoprotein that stimulates tyrosine phosphorylation of the Neu/HER-2 receptor and induces phenotypic differentiation of certain mammary cancer cell lines to growth-arrested and milk-producing cells. To determine which molecules participate in the concomitant morphological alterations, we analyzed the expression of several cytoskeletal and surface molecules and found that NDF elevated the expression of the intercellular adhesion molecule 1 (ICAM-1) in cultured AU-565 human adenocarcinoma cells. The levels of both the protein and the mRNA of ICAM-1 were elevated after 3-5 days of treatment with NDF. Elevated expression of ICAM-1 was induced also by gamma-interferon and by the tumor-promoting phorbol ester (PMA), albeit with different kinetics. Down-regulation of protein kinase C or its inhibition by calphostin C partially inhibited the effect of NDF, implying that the induction of ICAM-1 may be mediated by protein kinase C. NDF transcripts were detectable in 3 of 9 human mammary tumors, suggesting that the in vitro effect of the factor may be relevant to breast cancer. By selecting Neu-positive human mammary tumors (n = 39), we found a significant correlation (P < 0.001) between the expression of ICAM-1 and histological features of invasive ductal carcinoma with a prominent carcinoma in situ component. When cultured in vitro the cells of these tumors grew in clusters and formed domelike structures reminiscent of comedo-type carcinoma in situ. In addition, the majority of patients with tumors that coexpressed ICAM-1 and Neu had no lymph node involvement, unlike most Neu-positive but ICAM-1-negative tumors, which metastasized to the lymphatic system. Taken together, our observations suggest that the induction of ICAM-1 by NDF may affect the morphology, differentiation state, and metastasis of Neu-expressing mammary tumor cells.

Adenocarcinoma↗
PubMed1992

Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit.

We recently reported that a 44 kd glycoprotein secreted by transformed fibroblasts stimulates tyrosine phosphorylation of the product of the neu proto-oncogene and induces differentiation of mammary tumor cells to milk-producing, growth-arrested cells. A partial amino acid sequence of the protein, termed Neu differentiation factor (NDF), enabled cloning of the corresponding complementary DNA. The deduced structure of the precursor of NDF indicated that it is a transmembrane protein whose extracellular portion contains an EGF-like domain that probably functions as a receptor recognition site. In addition, the ectodomain contains one immunoglobulin homology unit. Despite the lack of a recognizable hydrophobic signal peptide at the N-terminus, a recombinant NDF, like the natural molecule, is released into the medium of transfected COS-7 cells in a biologically active form. Northern blot analysis indicated the existence of several NDF transcripts, the major ones being 1.8, 2.6, and 6.7 kb in size. Transformation by the ras oncogene dramatically elevated the expression of NDF in fibroblasts.

Amino Acid Sequence↗
PubMed1992

Tumor-inhibitory monoclonal antibodies to the HER-2/Neu receptor induce differentiation of human breast cancer cells.

The HER-2/neu protooncogene (also called erbB-2) encodes a tyrosine kinase receptor for a polypeptide growth-regulatory molecule. Amplification and overexpression of the gene have been frequently observed in human adenocarcinomas and correlated with poor prognosis. To explore the potential of antibody therapy directed at the HER-2/Neu receptor, we have raised a panel of murine monoclonal antibodies to the human protein, and tested their effect on the tumorigenic growth of HER-2/neu-transfected fibroblasts in athymic mice. We previously reported that the i.p. injected antibodies either inhibited or accelerated the tumorigenic growth of HER-2/neu transfectants in athymic mice. Here we report that these opposing effects were induced also by i.v. injected antibodies, they lasted over 7 weeks, and were probably mediated by distinct epitopes on the receptor molecule. To understand the cellular mechanisms underlying antibody-induced tumor inhibition, we tested the effect of the monoclonal antibodies on various cultured human breast cancer cells. Our analysis revealed that the tumor-inhibitory antibodies specifically induced phenotypic cellular differentiation that included growth arrest at late S or early G2 phase of the cell cycle, markedly altered cytoplasm and nuclear morphology, synthesis and secretion of milk components (casein and lipids), and translocation of the HER-2/Neu protein to cytoplasmic and perinuclear sites. The extent of cellular differentiation by various antibodies could be correlated with their tumor-inhibitory potential, whereas a tumor-stimulatory monoclonal antibody or control immunoglobulin were completely inactive with respect to cellular differentiation. Taken together, our in vivo and in vitro studies correlate the tumor inhibitory potential of monoclonal antibodies to HER-2/Neu with their capacity to induce cellular differentiation in vitro. This observation may hold promise for immunotherapy of cancers that express the HER-2/neu oncogene.

Animals↗
PubMed1992

Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells.

The neu/HER-2 proto-oncogene (also called erbB-2) encodes a transmembrane glycoprotein related to the epidermal growth factor receptor. We have purified to homogeneity a 44 kd glycoprotein from the medium of ras-transformed cells that stimulates phosphorylation of the Neu protein and retains activity after elution from the polyacrylamide gel. The protein is active at picomolar concentrations and displays a novel N-terminal sequence. Cross-linking experiments with radiolabeled p44 result in specific labeling of Neu, indicating that p44 is a ligand for Neu or a related receptor. The purified protein induces phenotypic differentiation of cultured human breast cancer cells, including altered morphology and synthesis of milk components. This is accompanied by an increase in nuclear area, inhibition of cell growth (probably by cell cycle arrest at the late S or the G2/M phases), and induction of DNA polyploidy. We propose the name Neu differentiation factor (NDF) for p44.

Amino Acid Sequence↗
PubMed1992

Ploidy analysis of epithelial ovarian cancers using image cytometry.

We used a computerized image analysis system to determine the DNA content of 103 epithelial ovarian cancers using touch imprints of frozen tumor samples. Similar to prior studies of ploidy using flow cytometry, we found that most ovarian cancers (78%) were aneuploid while a minority (22%) were diploid. There was no relationship between ploidy and stage, histologic grade, or the ability to perform optimal cytoreductive surgery. Also, like prior studies using flow cytometry, negative second-look laparotomy and survival were somewhat more common in advanced-stage patients with diploid cancers than in those with aneuploid cancers. We conclude that ploidy of ovarian cancers can be determined using a computerized image analysis system to quantitate feulgen staining of cells in touch imprints. Ploidy is unlikely to play a role in treatment planning for patients with advanced-stage disease. Larger studies of patients with early-stage disease are needed, however, to determine whether ploidy is a more accurate means of predicting which patients are most likely to benefit from adjuvant therapy.

Aneuploidy↗
PubMed1992

Prediction of response to adjuvant chemotherapy in premenopausal lymph node positive breast cancer patients with morphometry, DNA flow cytometry and HER-2/neu oncoprotein expression. Preliminary results.

The value of morphometry, DNA flow cytometry and HER-2/neu oncoprotein expression for prediction of response to adjuvant chemotherapy in premenopausal lymph node positive breast cancer patients was evaluated in a group of CMF treated patients and controls with long-term follow-up. In the treated group, the Morphometric Prognostic Index (cutpoint 1.1) was the best prognosticator (p less than 0.0001, MC = 16.9), followed by the Mitotic Activity Index, the volume percentage epithelium and the number of positive nodes. For the controls, only the % HER-2/neu oncoprotein expression revealed significant differences (p less than 0.0001, MC = 16.3). When directly comparing treated patients and controls stratified for a certain parameter, no significant differences were obtained, although a trend towards improved survival in the treated group was present for some of the subgroups for several parameters. These preliminary results indicate that morphometric features and quantitative HER-2/neu oncoprotein expression may be important factors for identifying cases that will or will not respond to adjuvant chemotherapy.

Adult↗
PubMed1992

A ligand for the erbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells.

The human erbB-2 oncogene encodes a tyrosine kinase receptor. A ligand for the erbB-2 receptor (gp30), with an apparent molecular weight of 30,000, was reported to modulate the growth of cells overexpressing erbB-2. Whereas low concentrations of gp30 induced proliferation of these cells, higher concentrations inhibited their growth. To elucidate the cellular mechanisms underlying cell growth inhibition by gp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells AU-565 and MDA-MB-453 (which overexpress erbB-2) and MCF-7 cells (which express low levels of this protooncogene). Ligand concentrations that inhibited growth in cells overexpressing erbB-2 induced apparent differentiation of cells with a more mature phenotype, i.e., with characteristics such as inhibited cell growth, altered cytoplasmic and nuclear morphology, and increased synthesis of milk components (casein and lipids). No significant effect of the ligand was observed in the human breast cancer cell line MCF-7. Concomitant with the induction of differentiation in AU-565 and MDA-MB-453 cells, the erbB-2 protein was translocated from membrane to the cytoplasm and perinuclear sites. These findings indicate that ligand-induced growth inhibition in cells overexpressing erbB-2 is associated with an apparent induction of differentiation.

Breast Neoplasms↗
PubMed1992

HER-2/neu oncogene expression, DNA ploidy and proliferation index in breast cancer.

HER-2/neu gene expression, DNA ploidy and proliferation index were studied in 250 cases of breast cancer. Expression of HER-2/neu was determined by using an antibody to the HER-2/neu receptor. Ki-67 antibody was used to determine the proliferation index of the breast cancers, and the Feulgen method was used to assess DNA amounts in the tumor cells. Histochemical staining was quantitated by image analysis. Of the cancers studied, 72 were positive for overexpression of HER-2/neu protein; of these, 62 (86%) possessed near-tetraploid DNA content, and 47 (65%) had more than one G0G1 stem line (polyploid) of DNA distribution. Cells from the cases negative for HER/2-neu overexpression contained DNA amounts that ranged from diploid to varying degrees of aneuploid. A significant difference in the amounts of cellular proliferation in HER-2/neu overexpressing cancers was found between those that expressed the HER-2/neu receptor on their membranes and those that exhibited mainly cytoplasmic receptors.

Breast Neoplasms↗
PubMed1991

Comparative long-term prognostic value of quantitative HER-2/neu protein expression, DNA ploidy, and morphometric and clinical features in paraffin-embedded invasive breast cancer.

Data regarding the prognostic value of HER-2/neu protein expression in breast cancer are conflicting, perhaps because of short follow-up and technical difficulties in the determination (the admixture of benign elements with the biochemical method and the subjectivity of the immunohistochemical assessment). Therefore, using digital image processing, we compared the correlation between and the prognostic value of (a) quantitative immunohistochemical HER-2/neu protein expression and (b) clinical, morphometric, and flow-cytometric DNA ploidy features; histologic grade; and biochemically assessed estrogen receptor content. Paraffin-embedded invasive breast Pancers of 82 patients with long-term follow-up were used. None of the patients had received adjuvant systemic therapy. HER-2/neu protein expression was significantly correlated with DNA index, lymph node status, and tumor size and, in the diploid tumors, was weakly correlated with the percentage of S-phase cells. Strong HER-2/neu protein expression was associated with a worse prognosis (although not significantly, p = 0.07). No differences were detected between cancers with or without axillary lymph node metastases. In survival analysis, the Multivariate Prognostic Index and the morphometric features were much stronger prognosticators than HER-2/neu protein overexpression, which, however, had additional prognostic value to that of many of the features analyzed, especially when more than 35% HER-2/neu protein levels (relative to the high expression SKBR3 cell line) were present. Combined diploidy and HER-2/neu protein content greater than 35% occurred in a small group of patients (n = 3), all of whom died. Likewise, in tetraploid cancers a combination of S-phase cells greater than or equal to 7% and HER-2/neu protein content greater than 35% was an ominous sign. In multivariate analysis, strong HER-2/neu protein overexpression was prognostically over-shadowed by the morphometric features. Nevertheless, it is important to further analyze the intriguing possibility of identifying a subgroup of breast cancer patients with a very poor outcome merely using cytometric analysis of paraffin-embedded material of the primary tumor.

Biomarkers, Tumor↗
PubMed1991

Quantitation of HER-2/neu oncoprotein overexpression in invasive breast cancer by image analysis: a study comparing fresh and paraffin-embedded material.

HER-2/neu oncoprotein overexpression was compared in fresh frozen and paraffin-embedded formalin-fixed invasive breast cancer material from the same patients. The HER-2/neu protein was detected by an immunohistochemical staining method, and the average amount of protein staining per cell was measured using the CAS-200 image analysis system and expressed relative to the amount of HER-2/neu protein of calibration cells of the SKBR3 cell line which are known to have amplification of the HER-2/neu gene and overexpression of the HER-2/neu protein. There was a significant correlation between degree of HER-2/neu protein overexpression and DNA-hyperdiploidy (P less than 0.01, chi 2 test). No significant correlation could be demonstrated between degree of HER-2/neu overexpression and tumor size, lymph node status, number of positive nodes or morphometric features. There was in general a good concordance (r = 0.83) in HER-2/neu expression values between fresh and paraffin-embedded material. Pairwise comparison of the two series (Wilcoxon signed ranks test) revealed no significant differences, indicating that there were no systematic differences between HER-2/neu assessments in fresh and paraffin material. When analysing the HER-2/neu expression values according to thresholds used earlier for overexpression, comparable results for fresh and paraffin material were obtained for most cases. In the fresh and paraffin material a different staining pattern was observed (more membrane staining in the fresh material in contrast to a more diffuse staining pattern in the paraffin material). It was concluded that both fresh-frozen and paraffin-embedded, formalin-fixed material is suitable for assessment of HER-2/neu protein overexpression by image analysis and provides comparable HER-2/neu expression values in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1990

Comparison of the Papanicolaou and Feulgen staining methods for DNA quantification by image analysis.

The possibility of using archival cytology material to study the evolution of neoplastic disease with regard to DNA content abnormalities was investigated. The accuracy of measuring the integrity optical density (OD) of nuclei that correlates to DNA amounts of those nuclei, on slides stained by the Papanicolaou method, was assessed and compared with a standard Feulgen method. Our data on rat liver nuclei peritoneal washings from patients with ovarian cystadenofibromas and ovarian cystadenocarcinomas suggested that analysis of cytological material using the Papanicolaou method is not reliable and that destaining the slides followed by Feulgen staining provides an optimal and reliable method of DNA quantification.

Adenofibroma↗
PubMed1990

Differentiation of cultured human breast cancer cells (AU-565 and MCF-7) associated with loss of cell surface HER-2/neu antigen.

The relationship between terminal cell differentiation and changes in the subcellular levels of the HER-2/neu antigen was investigated in cultured human breast cancer cells: AU-565 cells (which overexpress the HER-2/neu gene) and MCF-7 cells (which do not overexpress this gene). Differentiation was achieved by treating the cells with mycophenolic acid (MPA), phorbol 12-myristate 13-acetate (PMA), retinoic acid (RA), or the TA-1 monoclonal antibody to the extracellular domain of the HER-2/neu protein. Ten to twenty percent of the cells in untreated, sparsely growing AU-565 cultures exhibited morphological maturation characterized by large lacy nuclei surrounded by sizable flat cytoplasms. A fraction of these cells harbored milk factors such as casein and large lipid droplets. Treatment of the AU-565 cells for 4 d with 9 microM MPA, 1.6 nM PMA, 2.5 microM RA, or 1 microgram/mL TA-1 antibody resulted in cell growth inhibition and an increase in the percentage of cells (48-97%) that exhibit a mature phenotype. MCF-7 cells were also susceptible to differentiation by MPA and RA, but to a lesser degree than the AU-565 cells. Differentiation in the AU-565 and MCF-7 cells was associated with reduced immunostaining for the HER-2/neu protein at the cell surface membrane and with a transient increased diffuse immunostaining for this protein in the cytoplasm.

Blotting, Southern↗
PubMed1990

HER-2/neu oncogene expression and DNA ploidy analysis in breast cancer.

This study was performed to evaluate the correlation between HER-2/neu gene expression and DNA ploidy patterns. Forty-five cases of breast-cancer were analyzed. Immunohistochemical staining of HER-2/neu protein on frozen sections was used to detect the HER-2/neu protein, and the Feulgen DNA staining method was used to assess DNA amounts in the same tumor cells. Positive HER-2/neu overexpression was evaluated visually, and quantitation of the HER-2/neu protein was measured by image analysis. Twenty-two of the 45 cases were visually scored to be positive for the overexpression of the HER-2/neu protein, and these cases also contained above 10% HER-2/neu protein compared with a standard control cell line. All 22 of these cases had near-tetraploid DNA content. In contrast, cells, derived from the 23 cases that did not overexpress the HER-2/neu protein, contained DNA amounts that ranged from euploid (diploid) to varying degrees of aneuploid. The results of this study indicated that tumors that overexpress the HER-2/neu protein have tetraploid or near-tetraploid DNA content. This pattern could relate to the biological behavior of these tumors.

Adenocarcinoma↗
PubMed1990

HER-2/neu oncogene expression and proliferation in breast cancers.

Amplification of the HER-2/neu proto-oncogene in breast cancer has been reported to correlate with poor patient prognosis. The proliferation, or growth fraction, of cells has also been shown to be of prognostic importance in breast cancer. A study was conducted to evaluate the correlation between HER-2/neu gene expression and proliferation in breast cancer. Quantitative immunohistochemical methods for the detection of the HER-2/neu protein expression and for assessing the proliferation fraction on frozen sections of tumor cells were used. The detection of epidermal growth factor receptor (EGFR) along with quantitative DNA ploidy analysis, also was performed on the same breast cancers. The results indicated two subgroups of invasive ductal carcinoma; 1) HER-2/neu overexpressing cases that were negative for EGFR expression and had low proliferation fraction, and a tetraploid DNA pattern (22 cases), and 2) other combinations of HER-2/neu expression and EGFR expression, with a high proliferation fraction and an aneuploid DNA pattern (38 cases). Eight cases of carcinoma in situ were positive for HER-2/neu overexpression and negative for EGFR expression, and had a high proliferation fraction and a tetraploid DNA pattern. Twenty-six cases of low-grade carcinoma exhibited low proliferation and a diploid DNA pattern.

Breast Neoplasms↗
PubMed1989

Biological grading of breast cancer using antibodies to proliferating cells and other markers.

Quantitation of immunohistochemical staining by image analysis was performed on 50 breast cancers stained with the monoclonal antibody Ki-67 to determine the growth fraction and its correlation with tumor grade. A high degree of correlation was shown. For each case the DNA ploidy was determined by quantitation of the DNA Feulgen stain by computerized microdensitometry. DNA content of breast tumor cells correlated to the histopathologic grade at which poorly differentiated tumors are more likely to be aneuploid. Quantitation of immunohistochemistry for estrogen and progesterone receptors had a high degree of correlation with the steroid binding assay, such as dextran-coated charcoal assay (DCCA), and were weakly correlated to histologic grade. In summary, our results indicated that quantitation of Ki-67-positive nuclear area and of DNA content by image analysis provides an objective method for assessing tumor cell growth fraction and DNA ploidy. Quantitation of steroid receptors by immunohistochemistry is a better and easier technique than those currently used to determine the best therapy for postmenopausal women. These methods can be performed on small frozen sections or needle aspirates in quantities that are insufficient for current steroid binding assays. Thus, this method is prognosticly useful even for patients with small breast lesions.

Antibodies, Monoclonal↗