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PubMedDate not supplied

Beta-interferon, retinoids and tamoxifen combination in advanced breast cancer.

PURPOSE: To investigate, in patients with metastatic breast cancer (MBC), a combination of retinoids, beta-interferon (beta-IFN) and tamoxifen (TAM). PATIENTS AND METHODS: This trial was conducted from January 1987 to June 1992 in 85 consecutive patients with MBC. All patients had been treated for metastatic disease: 43 patients received chemotherapy, 35 received hormone therapy and 7 received both. Forty-nine patients, with a better prognosis, and a longer disease-free survival (DFS) were treated with beta-IFN 1 x 10(6) IU/m2 subcutaneously three times a week, TAM 10 mg TID, retinyl palmitate (R) 50,000 IU BID. Thirty-six patients with shorter DFS, were first treated with 8 courses of chemotherapy followed, in responders, by beta-IFN, R and TAM. RESULTS: With a median follow-up of 7 years (minimum 4 years) 59% of 85 evaluable patients responded, 20% had stabilization of disease and 21% progressed. Median response duration was 43 months. Median survival was 28 months and 25% of patients were alive after 9 years. Toxicity of biological therapy was moderate. CONCLUSIONS: Our data show that beta-IFN, TAM and R combination is effective as salvage therapy in patients with MBC.

Adult↗
PubMed2025

TamL is a Key Player of the Outer Membrane Homeostasis in Bacteroidota.

In Proteobacteria, the outer membrane protein TamA and the inner membrane-anchored protein TamB form the Translocation and Assembly Module (TAM) complex, which facilitates the transport of autotransporters, virulence factors, and likely lipids across the two membranes. In Bacteroidota, TamA is replaced by TamL, a TamA-like lipoprotein with a lipid modification at its N-terminus that likely anchors it to the outer membrane. This structural difference suggests that TamL may have a distinct function compared to TamA. However, the role of TAM in bacterial phyla other than Proteobacteria remains unexplored. Our study aimed to elucidate the function of TamL in Flavobacterium johnsoniae, an environmental Bacteroidota. Unlike its homologs in Proteobacteria, we found that TamL and TamB are essential in F. johnsoniae. Through genetic, phenotypic, proteomic, and lipidomic analyses, we show that TamL depletion severely compromises outer membrane integrity, as evidenced by reduced cell viability, altered cell shape, increased susceptibility to membrane-disrupting agents, and elevated levels of outer membrane lipoproteins. Notably, we did not observe an overall decrease in the levels of β-barrel outer membrane proteins, nor substantial alterations in outer membrane lipid composition. By pull-down assays, we found TamL co-purifying with TamB in F. johnsoniae, suggesting an interaction. Furthermore, we found that while TamL and TamB monocistronic genes are conserved among Bacteroidota, only some species encode multiple TamL, TamB and TamA proteins. To our knowledge, this study is the first to provide functional insights into a TAM subunit beyond Proteobacteria.

Bacterial Outer Membrane Proteins↗
PubMed1998

Human tumour-associated macrophages differentiate into osteoclastic bone-resorbing cells.

Macrophages are commonly found within osteolytic secondary carcinomas in bone, but the manner in which these cells contribute to malignant bone resorption is uncertain. Macrophages isolated from primary breast carcinomas were co-cultured for up to 21 days with UMR 106 rat osteoblast-like cells on bone slices and glass coverslips in the presence and absence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF). Cell cultures were then assessed for the presence of phenotypic markers of macrophage and osteoclast differentiation. Isolated cells were negative for osteoclast markers including tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and the ability to carry our lacunar bone resorption, but were positive for CD11b and CD14, macrophage markers which are not present on osteoclasts. In 21-day co-cultures of breast carcinoma tumour-associated macrophages (TAMs) and UMR 106 cells, incubated in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP- and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed. Contact with UMR 106 cells and the presence of 1,25(OH)2D3 and M-CSF were absolute requirements for differentiation of human breast carcinoma TAMs into mature functional osteoclasts. TAM-osteoclast differentiation may represent an important cellular mechanism of osteolysis in metastatic skeletal carcinomas.

Bone Neoplasms↗
PubMed1997

Natural interferon-alpha activity in hormone-sensitive, hormone-resistant and autonomous human breast-cancer cell lines.

This study explored the activity of natural interferon-alpha (nIFN-alpha) in regulating cell growth of 6 breast-cancer cell lines. The anti-proliferative effect of the combination nIFN-alpha and tamoxifen (TAM) or medroxyprogesterone acetate (MPA) in CG-5 estrogen-sensitive mammary cancer cells was investigated, and the ability of nIFN-alpha to restore hormone-sensitivity in the MPA-resistant MCF-7 SK sub-line was examined. nIFN-alpha, at concentrations ranging from 10 to 1000 IU/ml, inhibited cell proliferation of all cell lines tested after 3 and 6 days of treatment. In particular, the highest concentration of the drug used was equally effective in hormone-sensitive and in hormone-insensitive cells. A 6-day pretreatment of CG-5 cells with nIFN-alpha, at the above-mentioned doses, sensitized them to the growth-inhibiting activity of subsequent exposure to 10(-7) M TAM or MPA, which resulted in a synergistic effect, and could be explained on the basis of the observed enhancement of estrogen and progesterone receptors due to IFN activity. Conversely, the simultaneous drug combination did not modify the response to the hormone in CG-5 cells. Pre-treatment with nIFN-alpha (from 10 to 1000 IU/ml) restored MPA sensitivity in the MCF-7 SK sub-line, but no modulation of progesterone receptors was seen in this model. The hormone-sensitivity of the parental cell line was not substantially affected by pre-exposure to nIFN-alpha. These data indicate that nIFN-alpha may be potentially useful in enhancing the clinical effectiveness of TAM and MPA and in overcoming hormone resistance.

Antineoplastic Agents, Hormonal↗
PubMed1997

Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer.

Hormonal breast cancer therapies have traditionally been considered cytostatic, but recent pre-clinical data suggest that anti-oestrogens can induce apoptosis. The aim of this study was to assess whether tamoxifen (TAM) and ICI 182780 (ICI) could induce apoptosis in human breast cancer, and whether this was related to oestrogen receptor status. We measured apoptosis in primary breast cancer patients before and after pre-surgical treatment with 20 mg/day TAM (study 1) or 6 or 18 mg/day ICI (study 2). In each study there was a randomised non-treatment (NT) control group. TAM significantly increased apoptotic index (AI) in ER+ but not in ER- tumours. There was a significant increase in AI following treatment with ICI. Insufficient pairs of samples were available to determine whether this change was confined to ER+ tumours, but in a cross-sectional analysis AI was significantly higher in excision biopsies for ICI-treated than NT patients for ER+ but not ER- tumours. Our results provide clinical evidence that apoptosis may be induced in ER+ primary breast cancer by both non-steroidal and steroidal anti-oestrogens.

Adult↗
PubMed2001

Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma.

BACKGROUND: Macrophages often infiltrate into solid tumor tissues. Tumor-associated macrophages (TAMs) are known to play a crucial role in tumor progression. Monocyte chemoattractant protein-1 (MCP-1) is one of the major chemokines capable of inducing chemotactic migration of monocytes. METHODS: With the objective of investigating the clinical significance of MCP-1, the authors analyzed the expression of MCP-1 and of some other molecules by immunohistochemistry in 230 samples of primary breast carcinoma tissue. MCP-1 staining was performed using an anti-MCP-1 monoclonal antibody, and it was assessed by grading the percentage of stained cells. RESULTS: It was found that 117 breast tumor specimens (51%) had intensive staining in tumor cells. The expression of MCP-1 in tumor cells had a significant correlation with the expression of thymidine phosphorylase and membrane type 1-matrix metalloproteinase. In addition, MCP-1 expression tended to be associated with the accumulation of TAMs, which were counted by CD68 staining, and with microvessel density. MCP-1 expression in TAMs was correlated significantly with the histologic vessel invasion of tumor cells. CONCLUSIONS: The results of this study suggest that MCP-1 may play key roles in macrophage recruitment, in the expression of angiogenic factors, and in the activation of matrix metalloproteinases in patients with breast carcinoma.

Angiogenesis Inducing Agents↗
PubMed2002

Establishment and characterization of new murine breast cancer cell lines.

The establishment of two new breast cancer cell lines, MXT+ and MXT-, derived from the murine breast cancer models MXT-M-3,2 MC (hormone-sensitive) and MXT-M-3,2 (ovex) MC (hormone-insensitive), is described. Characterization of the cell lines was performed by investigation of morphology, steroid hormone receptor state, growth kinetics, and drug response as well as by cytogenetic analysis. MXT+ contains estrogen receptors (ER; 6.9 fmol/mg protein) as well as progesterone receptors (PgR; 9.2 fmol/mg protein) and therefore is inhibited by tamoxifen (Tam). MXT- proved to be ER- but PgR+ (23.4 fmol/mg protein) and, as expected, resistant against Tam. The sensitivity of MXT+ and MXT- against a pattern of therapeutically established anti-breast cancer drugs (cDDP, cisplatin; JM-8, carboplatin; DX, adriamycin; 5-FU, 5-fluorouracil; MTX, methotrexate; VLB vinblastine) was studied by use of a computerized, kinetic chemosensitivity assay based on quantification of biomass by staining cells with crystal violet. For each compound the inhibition profile reflecting cytostatic, transient cytotoxic, or cytocidal drug effects as well as development of resistance was evaluated. The following order of activity was found: MTX > VLB > or = DX > cDDP > or = 5-FU > JM-8. The test data of 5-FU, VLB, cDDP, and Tam on MXT+ as well as on MXT- were compared with those from studies on ER+ and ER- human breast cancer cell lines (MCF-7, ZR-75-1, T-47-D, and MDA-MB-231, respectively). They revealed comparable inhibition profiles and sensitivities of human and murine breast cancer cell lines, an indication that the results achieved in combined in vitro-/in vivo tests by use of the murine test models MXT+, MXT-, MXT-M-3,2 MC, and MXT-M-3,2(ovex) MC are relevant for therapy in humans.

Animals↗
PubMed2003

Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with Stage II and Stage III colon carcinoma: a role for the host response in prognosis.

BACKGROUND: The elucidation of new therapeutic targets of prognostic significance in colon carcinoma is necessary to improve outcomes. In the current study, the authors examined the expression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in primary colon carcinoma cases and VEGF in tumor-associated macrophages (TAM)/stroma, and their correlation with survival. METHODS: The authors identified 131 consecutive American Joint Committee on Cancer Stage II and Stage III colon carcinoma patients seen at the University of Rochester between 1990-1995. Expression of VEGF, EGFR, and CD68 were examined by immunohistochemistry in paraffin-embedded primary colon tumors and graded as the percentage of cells stained. Data were analyzed using a multivariate Cox proportional hazards model. RESULTS: VEGF expression in tumor was not found to be significantly associated with survival. However, 42% of the patients expressed VEGF in TAM/stroma. The median survival in this group was 9.7 years versus 4.3 years in the VEGF-negative (TAM/stroma) group (hazards ratio of 0.57, 95% confidence interval [95% CI], 0.34-0.95; P = 0.03). Although TAM infiltration alone was not found to be significant in multivariate analysis, the presence of both CD68 and VEGF (TAM/stroma) was predictive of improved survival (hazards ratio of 0.48, 95% CI, 0.28-0.83; P = 0.006). High grades of EGFR expression (> or = Grade 2) were found to be associated with a trend toward worsened survival. CONCLUSIONS: The greater than twofold increase in median survival associated with VEGF-expressing TAM suggests a hitherto unknown role for this subset of cells in the host response to colon carcinoma and requires further investigation. Overexpression of EGFR may be associated with worsened survival, providing a rationale for trials of anti-EGFR agents as adjuvant therapy.

Aged↗
PubMed1984

Phenotypes associated with tumor rejection mediated by cyclophosphamide and syngeneic tumor-sensitized T lymphocytes: potential mechanisms of action.

The phenotypes of the affector and effector cell populations involved during the induction of permanent tumor regression by combined therapy using cyclophosphamide (CY) and immune spleen cells were identified. Permanent tumor regression was dependent on the presence of Thyl+ Lyt-2+ lymphocytes in the immune spleen cell population that was injected i.v. 2-4 h after an intraperitoneal injection of CY (240 mg/kg) into C57BL/6J mice bearing 1.0-1.5 g. MCA/76-9 or MCA/76-64 sarcomas. Histological evaluation after the combined treatment indicated an intense influx of putative lymphocytes 6-10 days after the combined treatment, over and above the inflammatory response involving macrophages and neutrophils induced by CY treatment alone. These infiltrating cells were shown to be T lymphocytes, most of them having the Lyt-1 and Lyt-2 antigens on their cell membrane. Isolated MCA/76-9 or 76-64 tumor-associated cells (TAC), lymphocytes (TAL) and macrophages (TAM) inhibited MCA/76-9 or 76-64 tumor growth respectively in a Winn test in an immunologically specific manner, having no effect on the growth of the B6 sarcoma cells, MCA/76-45 and 77-23. The tumor-free mice from the Winn test were not resistant to a subsequent challenge inoculum of either MCA/76-9 or 76-64 cells. Isolated TAC were usually non-specifically cytotoxic in vitro, while TAL and TAM showed some degree of specificity. The overall data indicated that the ultimate rejection of those tumor cells remaining after the direct anti-tumor action of CY had been dissipated was probably mediated by the combined action of TAL and TAM.

Animals↗
PubMed1988

Macrophages associated with murine tumours express plasminogen activator activity.

The fibrinolytic activity of cancer cells has been repeatedly implicated in mechanisms of local spread and tumour invasiveness. Mononuclear phagocytes associated with solid tumours might also contribute to fibrin dissolution at the tumour/host interface through the expression of plasminogen activator (PA) activity. We have investigated the PA activity of tumour-associated macrophages (TAM) from 4 transplanted murine tumours in syngeneic hosts; peritoneal macrophages (native and thioglycolate-elicited) from both tumour-bearing and control animals were studied as reference cells. TAM from 3 tumours (MSV, mFS6, MN/MCAI) had basal levels of PA activity (20% plasminogen-independent) comparable to or higher than those of thioglycolate-elicited peritoneal macrophages from the same tumour-bearing animals. TAM isolated from 1 tumour (MS2) had a PA which was very low (60% plasminogen-independent), but higher than the activity of unstimulated peritoneal macrophages. Molecular analysis of PA by SDS-PAGE electrophoresis and fibrin autography revealed in all macrophages a single species having an apparent MW of 48 kDA. It thus appears that, in some experimental neoplasms, tumour cell vicinity may represent an in vivo stimulus for macrophage PA expression.

Animals↗
PubMed1990

Type-II estrogen binding sites in a lymphoblastoid cell line and growth-inhibitory effect of estrogen, anti-estrogen and bioflavonoids.

Type-II estrogen-binding sites (type-II EBS) have been demonstrated in the human lymphoblastoid cell line IM-9 using a whole-cell assay with (6,7-3H) estradiol (3H-E2) as tracer. Competition analysis showed that the anti-estrogen tamoxifen and the flavonoids quercetin and rutin competed for (3H)-E2 binding to type-II EBS. Growth experiments demonstrated that diethylstilbestrol (DES) tamoxifen (TAM), quercetin and rutin exerted a reversible dose-dependent inhibition of cell proliferation in the range of concentrations between 10 nM and 10 microM. The relative binding affinity of quercetin, rutin, DES and TAM for type-II EBS correlated well with their potency as cell growth inhibitors. Moreover, hesperidin, a flavonoid which does not bind to type-II EBS, was ineffective in inhibiting cell growth. Cell-cycle analysis showed that the growth-inhibitory effect of DES, TAM or quercetin was due to a blocking effect in the G0-G1 phases. Our results suggest that high estrogen and anti-estrogen concentrations and flavonoids may regulate IM-9 cell growth through a common mechanism involving a binding interaction with type-II EBS.

Binding, Competitive↗
PubMed2006

RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells.

Insulin receptor substrate 1 (IRS-1) is a major downstream signaling protein for insulin and insulin-like growth factor I (IGF-I) receptors, conveying signals to PI-3K/Akt and ERK1/2 pathways. In breast cancer, IRS-1 overexpression has been associated with tumor development, hormone-independence and antiestrogen-resistance. In part, these effects are related to potentiation of IRS-1/PI-3K/Akt signaling. In estrogen sensitive breast cancer cell lines, tamoxifen treatment reduces IRS-1 expression and function; consequently, inhibiting IRS-1/PI-3K signaling. We tested whether anti-IRS1 siRNA could inhibit growth and survival of estrogen-sensitive MCF-7 breast cancer cells, when used alone or in combination with TAM. Our results indicated: (a) out of four tested anti-IRS1 siRNAs, two siRNAs reduced IRS-1 protein by approximately three-fold in both growing and IGF-I-stimulated cells without affecting a closely related protein, IRS-2; (b) these effects paralleled IRS1 mRNA downregulation by approximately three-fold, measured by quantitative real time-polymerase chain reaction; (c) action of anti-IRS1 siRNAs induced the apoptotic response, observed by altered mitochondrial membrane potential coupled with downregulation of NF-kappaB target Bcl-xL and reduced cell viability; (d) anti-IRS1 siRNA treatment enhanced the cytotoxic effects of TAM by approximately 20%. In summary, anti-IRS1 RNAi strategy could become a potent tool to induce breast cancer cell death, especially if combined with standard TAM therapy.

Breast Neoplasms↗
PubMed1987

Defective production of reactive oxygen intermediates by tumor-associated macrophages exposed to phorbol ester.

Macrophages were isolated from poorly immunogenic metastatic sarcomas (mFS6 and MN/MCA1) of C57BL/6 origin. Tumor-associated macrophages (TAM) showed little release of superoxide when exposed to phorbol myristate acetate. When exposed to a phagocytic stimulus (zymosan), TAM released appreciable amounts of superoxide. TAM had a lower number of specific binding sites for phorbol esters than resident or caseinate-elicited peritoneal macrophages, but had normal NADPH-cytochrome C reductase. The tumor environment, possibly through previously demonstrated products of neoplastic cells, may influence the functional status of in situ macrophages and, thus, impair host anti-tumor and anti-microbial defense mechanisms.

Animals↗
PubMed1991

Tumor-associated macrophages share in vitro growth characteristics with resident but not elicited macrophages.

Recent studies have shown that tissue macrophages are capable of proliferation and that this capability is enhanced by various cytokines, including macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Tumor-associated macrophages (TAM) have been demonstrated to proliferate in vitro, but no information is currently available on the ability of M-CSF and GM-CSF to enhance this response. To address this problem, limiting dilution analysis was utilized to examine the proliferative ability of macrophages isolated from two murine tumors of distinct origin following growth in secondary hosts. As a means of comparison, resident peritoneal macrophages (RPM) and thioglycolate-elicited macrophages (TEM) were also analyzed. Results indicate that a rare subset of TAM and RPM is capable of proliferation and that M-CSF and GM-CSF enhance the frequency of TAM and RPM which proliferate, but do not enhance the growth of TEM.

Animals↗
PubMed2002

Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry.

The structural relaxation time is a measure of the molecular mobility involved in enthalpy relaxation, and thus, is a measure of the dynamics of amorphous (glassy) pharmaceutical solids that determines physicochemical properties and reactivity of drugs in amorphous formulations. In this article we describe a novel method for characterization of structural relaxation using isothermal microcalorimetry, which directly measures the rate of heat release during the relaxation processes. The structural relaxation time is then obtained from a fit of the power data to the derivative version of the Kohlrausch-Williams-Watts (KWW) equation. The relaxation times of quenched and lyophilized samples of saccharides were studied using an isothermal microcalorimeter, the Thermal Activity Monitor (TAM). In addition to the KWW derivative function, a derivative equation of the modified stretched exponential function (MSE) was employed to evaluate TAM data. The later (MSE) appeared to have numerical advantages over the KWW equation. The data demonstrate, as expected, that structural relaxation times of amorphous solids depend on a number of variables, including nature of material, temperature, moisture content, thermal history, etc. Isothermal microcalorimetry with the TAM provides a very fast and reliable way to characterize the dynamics of glassy materials, which in many respects is superior to the conventional DSC approach. To the extent stability and structural relaxation dynamics in the glass are correlated, structural relaxation parameters derived by isothermal microcalorimetry may provide data useful for rational development of stable peptide and protein formulations and for the control of their processing.

Algorithms↗
PubMed1992

Antitumor effect of triphenylethylene derivative (TAT-59) against human breast carcinoma xenografts in nude mice.

The antitumor activity of a newly synthesized triphenylethylene derivative [(E)-4-[1-[4-[2-(dimethylamino)ethoxy-phenyl]-2-(4-isopropyl)phenyl-1- butenyl] phenyl monophosphate] (TAT-59) was investigated against human breast carcinoma xenografts in nude mice with reference to the changes of hormone receptors. Five strains (MCF-7, Br-10, R-27, ZR-75-1, and T-61) used for the experiments possessed cytosol estrogen receptor (ER), and their growth was estradiol dependent. Five mg of TAT-59 and tamoxifen citrate (TAM) per kg were administered p.o. daily except Sunday. TAT-59 showed a positive antitumor effect against MCF-7 and R-27, whereas TAM was effective on MCF-7, and their adverse effects detected by mortality rate, body weight loss, and spleen weight loss were similar to each other. The reduction of ER and production of progesterone receptor (PgR) after the treatment with TAT-59 were more potent than after TAM, suggesting that TAT-59 exerts its antitumor effect through binding to ER. These findings suggest that TAT-59 might merit use in clinical trials with breast cancers.

Animals↗
PubMed1999

Distinct effects on the conformation of estrogen receptor alpha and beta by both the antiestrogens ICI 164,384 and ICI 182,780 leading to opposite effects on receptor stability.

Tissue-specific effects of 17beta-estradiol (E(2)) and synthetic estrogen receptor (ER) ligands on target gene regulation might, at least partly, be explained by a selective ligand-induced conformational change of their receptors (ERalpha and ERbeta). In this study, the effects of E(2) and the synthetic ER ligands tamoxifen (TAM), ICI 164,384, and ICI 182,780 on the conformation of ERalpha and ERbeta were examined using limited proteolytic digestion analysis. We found that E(2) induced a conformational change of ERalpha resulting in the protection of a 30-kDa product, whereas TAM protected a 28-kDa fragment. Strikingly, the ERalpha conformational change induced by both ICI 164,384 and ICI 182,780 did not result in protection but rather seems to induce a ligand concentration-dependent increase in proteolytic degradation of the 30- and 28-kDa products. Incubation of ERbeta with E(2) resulted in an increased protection of a 30-kDa fragment, whereas with TAM protection of a 29-kDa fragment was observed. In contrast to the situation with ERalpha, ICI 164,384 and ICI 182,780 incubation induced the protection in a manner similar to 30-kDa fragment E(2). In addition, the ICI compounds also induced in a dose-dependent manner the preservation of a 32-kDa fragment. Our observations demonstrate that ICI 164,384 and ICI 182,780 have distinct effects on the conformation of ERalpha and ERbeta, resulting in receptor subtype-selective opposite effects on receptor stability in vitro.

Dose-Response Relationship, Drug↗
PubMed2001

Lactoferrin: a tamoxifen-responsive protein in normal and malignant human endometrial cells in culture.

We investigated the possible role of the estrogen-regulated protein lactoferrin (Lf) in the response of isolated normal human endometrial epithelial cells (NHEC) and established human endometrial carcinoma (EC) cell lines to tamoxifen (TAM). Using confocal laser scanning microscopy and a monospecific antibody, Lf was localized to the cytoplasm of normal and EC cells. Antibody neutralization of secreted Lf inhibited, whereas exogenous Lf (0--100 microg/ml) enhanced, cell proliferation in both classes of cells. Treatment of NHEC with TAM inhibited cell growth via a protein kinase-C-mediated pathway, concomitant with a reduction in the staining intensity for Lf. Importantly, in EC cells, TAM greatly enhanced the staining intensity for Lf, but did not affect cell growth. We propose that stable expression of Lf protein by EC cells may impart a survival advantage to these cells, which may, in part, account for the resistance of these cells to tamoxifen.

Animals↗