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Biomedical subjects

N E Davidson

Publications and source records attributed to N E Davidson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Novobiocin in combination with high-dose chemotherapy for the treatment of advanced breast cancer: a phase 2 study.

We conducted the first phase 2 and pharmacologic study to evaluate the combination of novobiocin (a coumeromycin antibiotic that has been shown to augment alkylating agent cytotoxicity in experimental models) and high-dose cyclophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure the ability of novobiocin to reverse alkylator drug resistance in vitro. Forty-one women with chemotherapy-responsive advanced breast cancer received cyclophosphamide (4 g/m2) for peripheral blood stem cell mobilization (treatment 1) followed by high-dose cyclophosphamide (1.5 g/m2 per day for 4 days), thiotepa (200 mg/m2 per day for 4 days), and novobiocin (4 g/day orally for 7 days) (treatment 2) and autologous marrow support. The median PFS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-70.6 months). There was no statistically significant relationship between PFS or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4-hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during novobiocin therapy were able to reverse alkylator drug resistance in an in vitro colony-forming assay. Correlative laboratory studies in an in vitro model system demonstrated that patient plasma after novobiocin treatment resulted in the magnitude of resistance reversal that had been predicted by prior preclinical experiments. Clinically, however, this activity of novobiocin did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.

Adult↗
PubMed2000

Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral blood progenitor cells.

The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received cyclosporine (CsA) 2.5 mg kg-1 i.v. daily, d 0-28, and interferon-gamma (IFNg) 0.025 mg/m2 s.c. qod, d7-28, following PBPC-T +/- bone marrow transplantation (BMT). Preceding high-dose chemotherapy consisted of cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2. Histologically proven > or = grade II cutaneous GVHD was induced in18/50 (36%) of patients and was independent of the source of haematopoietic support. In vitro studies showed that post-transplant, 76% of patients had developed auto-cytotoxicity against their own pre-transplant PHA-lymphoblasts. A significant correlation between the occurrence of GVHD > or = grade II and cytolysis was observed in the NK cell-line K562 and the T47D breast cancer cell-line. With a median follow-up of 2(1/2) years, the overall survival (OS) is 58%, the disease-free survival (DFS) 26%, both independent of the development of GVHD and similar to what has been observed in other studies on high-dose chemotherapy in advanced breast cancer. It therefore remains unclear whether the induction of autologous GVHD with the occurrence of auto-cytotoxic lymphocytes can result in an anti-tumour effect in this group of patients.

Adult↗
PubMed2000

Primary systemic therapy in operable breast cancer.

PURPOSE: Laboratory studies suggest that primary systemic therapy (PST) could improve control of micrometastatic disease and impact on overall survival (OS). This article examines the rationale for and preclinical and clinical data of PST in operable breast cancer and the potential role of intermediate biomarkers as predictive and/or prognostic factors for response and survival. DESIGN AND METHOD: We conducted an extensive literative review (including MEDLINE) on preclinical studies, single-arm feasibility studies, large randomized single- and multi-institutional trials, and laboratory correlate studies of PST in breast cancer. RESULTS: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PST for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significant (less than 10%) absolute increase in the use of breast-conservation treatment (BCT) with similar rates of local control. Although one study showed better disease-free survival (DFS) and another showed better OS, most studies did not show any survival advantage of primary versus adjuvant systemic therapy. Thus far, pathologic complete response seems to be the best predictor of survival, but clinical response assessment correlates poorly with pathologic response. Pilot studies demonstrated feasibility of procuring tissue at diagnosis and after treatment for assays of potential intermediate biomarkers. Initial data suggest a potential correlation between markers of proliferation and apoptosis and in vivo chemotherapy sensitivity. CONCLUSION: Thus far, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing trials should determine if specific subsets of patients at risk would benefit from additional systemic therapy and the potential role of intermediate biomarkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strategies should not replace standard adjuvant approaches. Rather, they represent an acceptable alternative to women with palpable, operable tumors and an excellent arena for clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Effects of the polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaundecane and N1-ethylN-11-((cycloheptyl)methyl)-4,8-diazaundecane in human prostate cancer cells.

The high levels of polyamines maintained in the prostate suggest that these compounds are important to prostate cell function and that disruption of polyamine metabolism may be an effective way to stop the growth of prostate cancer cells. The unsymmetrically alkylated polyamine analogues N1-ethyl-N11-((cyclopropyl)methyl)-4,8-diazaunde-cane (CPENSpm) and N1-ethyl-N11-((cycloheptyl)methyl)-4,8-diazaundecane (CHENSpm) have been shown previously to have cytotoxic effects in breast and non-small cell lung cancer cells. We have now investigated the responses of three human prostate cancer cell lines, LNCaP, PC3, and Du145, to these polyamine analogues and to the symmetrically alkylated analogue N1,N11-bis(ethyl)norspermine (BE 3-3-3). The Du145 cell line, in which IC50 values ranged from 0.65 to 0.8 microM, was the most sensitive to each of the polyamine analogues, although significant growth inhibition resulted in the other cell lines as well. CPENSpm and BE 3-3-3 but not CHENSpm caused significant decreases in the intracellular spermine and spermidine pools, although all three analogues accumulated to high levels in each of the cell lines. Spermidine/spermine N1-acetyltransferase activity was induced 23-250-fold in response to CPENSpm and BE 3-3-3, but it was not affected by CHENSpm. None of the analogues had significant effects on the activities of ornithine decarboxylase or S-adenosylmethionine decarboxylase. Quantitation of DNA fragmentation indicative of programmed cell death (PCD) showed that both CPENSpm and CHENSpm were effective inducers of PCD in all three prostate cell lines. In contrast, BE 3-3-3 led to PCD only in LNCaP cells. The ability to induce PCD was the only parameter measured that correlated with cell line sensitivity to these polyamine analogues.

Antineoplastic Agents↗
PubMed2000

Delayed micromolar elevation in intracellular calcium precedes induction of apoptosis in thapsigargin-treated breast cancer cells.

Thapsigargin (TG), a highly specific inhibitor of the sarcoplasmic reticulum and endoplasmic reticulum Ca2+-ATPase pump, can induce apoptosis in a variety of epithelial and lymphoid cell types. In prostate cancer cell lines, TG induces an initial 5- to 10-fold elevation of intracellular calcium ([Ca2+]i) within a few minutes of exposure. With prolonged exposure times (i.e., 12-36 h) a second elevation of [Ca2+]i to >10 microM is observed. In this study, the human breast carcinoma cell lines MCF-7 and MDA MB 468 cells were used to determine the temporal relationship between TG-induced elevation of [Ca2+]i and activation of programmed cell death. Using a microinjection method that allows for long-term analysis of [Ca2+]i changes, we found that after TG exposure, calcium measurements in these cells demonstrated an initial rise (>4-fold) in [Ca2+]i that occurred within minutes and returned to baseline within a few hours. With prolonged TG exposure, the cells underwent a second elevation (>5 microM) of [Ca2+]i occurring stochastically between 12 and 36 h after the initial exposure to TG. Both of the cell lines were growth-inhibited by 100 nM TG after only 1 h of exposure, but clonogenic ability in the MCF-7 cells was significantly reduced only after 48 h of exposure. The induction of apoptosis by TG was demonstrated by morphological changes typical for programmed cell death and DNA fragmentation (both high molecular weight and oligonucleosomal-sized fragments were detected) after 48 h of treatment. TG induction of apoptosis in these breast cancer cells occurred subsequent to the secondary rise in [Ca2+]i, which confirmed that this secondary rise in [Ca2+]i is not prostate cancer-specific. The secondary rise in [Ca2+]i to micromolar levels may directly activate the endonucleases responsible for DNA fragmentation that occurs as part of the apoptotic process. These studies indicate that TG is an active agent in vitro against breast cancer cells. Inactive prodrug analogues of TG are currently being developed that can be activated by tissue-specific proteases, and further pursuit of this strategy as a potential treatment for breast cancer is warranted.

Apoptosis↗
PubMed2000

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Breast Neoplasms↗
PubMed1999

Expression of DNA methyl-transferase (DMT) and the cell cycle in human breast cancer cells.

Estrogen receptor (ER)-negative breast cancer cells display extensive methylation of the ER gene CpG island and elevated DNA methyltransferase (DMT) expression compared to ER-positive cells. The present study demonstrates that DMT protein levels tightly correlate with S phase fraction in ER-positive cells, whereas ER-negative cells express DMT throughout the cell cycle. In addition, levels of p21CIP1, which disrupts DMT binding to PCNA, are inversely correlated with DMT levels. Therefore increased DMT expression in ER-negative cells is not simply due to elevated S-phase fraction, but rather to more complex changes that allow cells to escape normal cell cycle-dependent controls on DMT expression. Because ER-negative breast tumors often have activated growth factor pathways, the impact of these pathways on DMT expression was examined in ER-positive cells. Stable transfection with fibroblast growth factors (FGFs) 1 and 4 led to increased DMT expression that could not be accounted for by a shift in S phase fraction. Elevated DMT protein expression in FGF-transfectants was accompanied by a significant decrease in p21, again suggesting a reciprocal relationship between these two proteins. However, acquisition of an estrogen-independent phenotype, even in conjunction with elevated DMT levels, was not sufficient to promote ER gene silencing via methylation. These results indicate that multiple steps are required for de novo methylation of the ER CpG island.

Amino Acid Sequence↗
PubMed1999

Comparison of paclitaxel-, 5-fluoro-2'-deoxyuridine-, and epidermal growth factor (EGF)-induced apoptosis. Evidence for EGF-induced anoikis.

Epidermal growth factor (EGF), a hormone that stimulates proliferation of many cell types, induces apoptosis in some cell lines that overexpress the EGF receptor. To evaluate the mechanism of EGF-induced apoptosis, MDA-MB-468 breast cancer cells were examined by microscopy, flow cytometry, immunoblotting, enzyme assays, and affinity labeling after treatment with EGF, paclitaxel, or 5-fluoro-2'-deoxyuridine (5FUdR). Apoptosis induced by all three agents was accompanied by activation of caspases-3, -6, and -7, as indicated by disappearance of the corresponding zymogens from immunoblots, cleavage of substrate polypeptides in situ, and detection of active forms of these caspases in cytosol and nuclei using fluorogenic assays and affinity labeling. Further analysis indicated involvement of the cytochrome c/Apaf-1/caspase-9 pathway of caspase activation, but not the Fas/Fas ligand pathway. Interestingly, caspase activation was consistently lower after EGF treatment than after paclitaxel or 5FUdR treatment. Additional experiments revealed that the majority of cells detaching from the substratum after EGF (but not paclitaxel or 5FUdR) were morphologically normal and retained the capacity to readhere, suggesting that EGF-induced apoptosis involves cell detachment followed by anoikis. These observations not only indicate that EGF- and chemotherapy-induced apoptosis in this cell line involve the same downstream pathways but also suggest that detachment-induced apoptosis is responsible for the paradoxical antiproliferative effects of EGF.

Affinity Labels↗
PubMed1999

Long term follow-up of women treated with 16-week, dose-intensive adjuvant chemotherapy for high risk breast carcinoma.

BACKGROUND: A Phase II study was performed evaluating the disease free and overall survival rates associated with a dose-intensive, 16-week, doxorubicin-based adjuvant chemotherapy regimen in women with breast carcinoma and > or = 10 involved axillary lymph nodes. METHODS: Eligible patients underwent staging with computed tomography and bone scanning and were treated with a 16-week, dose-intensive chemotherapy regimen, comprised of 8 2-week courses of cyclophosphamide, 100 mg/m2 orally, on Days 1-7; doxorubicin, 40 mg/m2 intravenously (i.v.), on Day 1; methotrexate, 100 mg/m2 i.v., on Day 1 with leucovorin rescue, 10 mg/m2, every 6 hours for 6 doses orally on Day 2; vincristine, 1 mg i.v. on Day 1; 5-fluorouracil (5-FU), 600 mg/m2 i.v., on Day 2 over 2 hours; and 5-FU, 300 mg/m2/day continuous i.v. on Days 8 and 9. Tamoxifen, 20 mg daily, was administered to patients with estrogen receptor positive tumors treated after October 1988. All patients were offered locoregional radiation therapy. RESULTS: Sixty-four women were treated on protocol. The median follow-up of 27 surviving patients was > 8 years at last follow-up. Three patients were lost to follow-up. The median time to progression was 54 months, the Kaplan-Meier estimate of event free survival at 5 years was 44% (95% confidence interval [CI], 31-56%), and the Kaplan-Meier estimate of overall survival at 5 years was 57% (95% CI, 44-69%). At 98 months the Kaplan-Meier estimate of freedom from recurrence was 31% (95% CI, 19-43%) and the Kaplan-Meier estimate of survival at 111 months was 36% (95% CI, 23-49%). CONCLUSIONS: Despite the use of dose-intensive, doxorubicin-based, adjuvant chemotherapy, and intensive staging prior to study entry, the results of the current study are similar to those of previous reports for standard dose chemotherapy and appear inferior to those reported for high dose therapy.

Adult↗
PubMed1999

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer.

PURPOSE: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. METHODS: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, methotrexate 100 mg/m2 on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m2 for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m2 with the vinorelbine dose held at its MTD. RESULTS: total of 98 courses of treatment (median of 4 per patient, range 2-8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m2, doxorubicin 40 mg/m2, and methotrexate 100 mg/m2 with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%-38%), 5 partial responses (25%, 95% confidence interval 9%-49%) and an overall response rate of 40% (95% confidence interval 19%-64%). The median survival was estimated to be 25 months from the start of chemotherapy. CONCLUSIONS: Vinorelbine at 25 mg/m2 can be safely administered with doxorubicin at 40 mg/m2 and methotrexate at 100 mg/m2 with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin.

Adult↗
PubMed1999

New data on adjuvant therapy for breast cancer.

In the past year, the results of the third Oxford Overview and recommendations from the St. Gallen International Consensus Panel on adjuvant treatment for breast cancer were published. Reports of trials addressing the role of anthracyclines and taxanes, as well as the optimal dosing schedule for cyclophosphamide, methotrexate, and 5-fluorouracil, also appeared. Data show that primary therapy increases the rate of breast conservation but not survival rates. The initial results of trials of high-dose chemotherapy with autologous hematopoietic support have been mixed. The usefulness of sentinel node biopsy in minimizing surgical morbidity and of biologic markers in predicting response to adjuvant therapy are areas of active research.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

The biology of breast cancer.

This article focuses on the major hormones and growth factors for which a critical role in normal mammary growth has been clearly defined. Certainly other hormonal systems and growth factors could also affect breast cancer initiation and progression, but their exact contribution to normal and/or malignant breast cell growth is poorly delineated. Examples of such factors include somatostatin, mammostatin, mammary-derived growth inhibitor (MDGI), mammary-derived growth factor-1 (MDGF-1), inhibins, activins, androgens, glucocorticoids, vitamin D, thyroid hormones, ecosinoids, and oxytocin. Clearly, the hormonal regulation of breast cancer cell growth and survival is multifaceted and very complex. In particular, the effects of estrogens and anti-estrogens on breast cells may depend on their interaction with a wide variety of other pathways. In addition, these interactions may vary among individual breast tumors depending on other genetic changes in the tumor cells that have not been discussed here, such as oncogene activation and loss of tumor suppressors. A more detailed understanding of how cells circumvent a dependency on these pathways is greatly needed in order to identify new biological targets and to design novel therapies for breast cancers that are resistant to anti-estrogen therapy. Such agents could be used alone or in combination with anti-estrogens to improve response to a second course of hormonal therapy.

Breast↗
PubMed1999

American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines.

OBJECTIVE: To determine an effective, evidence-based, postoperative surveillance strategy for the detection and treatment of recurrent breast cancer. Tests are recommended only if they have an impact on the outcomes specified by American Society of Clinical Oncology (ASCO) for clinical practice guidelines. POTENTIAL INTERVENTION: All tests described in the literature for postoperative monitoring were considered. In addition, the data were critically evaluated to determine the optimal frequency of monitoring. OUTCOME: Outcomes of interest include overall and disease-free survival, quality of life, toxicity reduction, and secondarily cost-effectiveness. EVIDENCE: A search was performed to determine all relevant articles published over the past 20 years on the efficacy of surveillance testing for breast cancer recurrence. These publications comprised both retrospective and prospective studies. VALUES: Levels of evidence and guideline grades were rated by a standard process. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. BENEFITS, HARMS, AND COSTS: The possible consequences of false-positive and -negative tests were considered in evaluating a preference for one of two tests providing similar information. Cost alone was not a determining factor. RECOMMENDATIONS: The attached guidelines and text summarize the updated recommendations of the ASCO breast cancer expert panel. Data are sufficient to recommend monthly breast self-examination, annual mammography of the preserved and contralateral breast, and a careful history and physical examination every 3 to 6 months for 3 years, then every 6 to 12 months for 2 years, then annually. Data are not sufficient to recommend routine bone scans, chest radiographs, hematologic blood counts, tumor markers (carcinoembryonic antigen, cancer antigen [CA] 15-5, and CA 27.29), liver ultrasonograms, or computed tomography scans. VALIDATION: The recommendations of the breast cancer expert panel were evaluated and supported by the ASCO Health Services Research Committee reviewers and the ASCO Board of Directors.

Breast Neoplasms↗
PubMed1999

Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group.

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

Adult↗
PubMed1999

Clinical aspects of cell death in breast cancer: the polyamine pathway as a new target for treatment.

Because intracellular polyamines have a critical role in cell proliferation and death pathways, the polyamine metabolic pathway represents a potential target for intervention in cancers. A number of polyamine analogues have been identified that downregulate polyamine synthesis and enhance polyamine catabolism, thereby depleting intracellular polyamines. Treatment of human breast cancer cell lines in culture with these analogues has been shown to decrease cell proliferation and induce programmed cell death. Phase I studies with one analogue are now complete, setting the stage for phase II trials to determine efficacy, in addition to preclinical studies to examine combinations of polyamine analogues and conventional cytotoxics.

Acetyltransferases↗
PubMed1998

Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression.

Progesterone receptor (PR) is an estrogen-stimulated gene which has a CpG island that is heavily methylated in a significant fraction of estrogen receptor (ER)-negative/PR-negative human breast cancers and cell lines, including MDA-MB-231 cells. Treatment of MDA-MB-231 cells with the demethylating agent, 5-aza-2'-deoxycytidine (deoxyC) led to demethylation and expression of ER and PR. However, simultaneous treatment with antiestrogen prevented PR transcription, suggesting that demethylation of PR alone is not sufficient to reactivate the PR gene. To examine the effects of ER on the methylation status of the PR CpG island, we stably transfected MDA-MB-231 cells with an inducible expression vector for ER. Surprisingly, in two cell clones, we found that induction of PR gene expression by ligand-bound ER does not require demethylation of the PR CpG island. In contrast, induction of PR transcription was inhibited by blocking the interaction of ER with SRC-1A, a coactivator of ER function. For the first time, we show that a transcription factor with the potential to remodel heterochromatin can activate gene expression without altering the methylation status of the CpG island. These results raise the possibility that demethylation and histone acetylation are distinct but complementary mechanisms for destabilizing heterochromatin and activating transcription.

Azacitidine↗
PubMed1998

Mapping of ER gene CpG island methylation-specific polymerase chain reaction.

Southern analysis has shown that DNA from 25% of primary estrogen receptor (ER) alpha-negative breast tumors displays aberrant methylation at one site within the ER gene CpG island. To examine more sites and increase sensitivity, we developed a methylation-specific PCR assay to map methylation of the entire ER CpG island. The island was unmethylated in normal breast tissue and ER-positive breast cancer cell lines, but extensively methylated in all ER-negative cell lines and breast tumors examined. In addition, some of the ER-positive/progesterone receptor-negative and ER-positive/progesterone receptor-positive tumors (about 70% and 35%, respectively) displayed methylation of the ER CpG island, suggesting that this heterogeneity within tumor cell populations could potentially shed light on the etiology of ER-negative recurrent tumors arising from ER-positive tumors.

Adult↗