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Biomedical subjects

C K Osborne

Publications and source records attributed to C K Osborne.

At least 19 recordsLinked to original sources
PubMed2003

Fulvestrant (Faslodex) versus anastrozole for the second-line treatment of advanced breast cancer in subgroups of postmenopausal women with visceral and non-visceral metastases: combined results from two multicentre trials.

The efficacy of fulvestrant (Faslodex), a novel oestrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, was compared with the aromatase inhibitor anastrozole (Arimidex) for the second-line treatment of advanced breast cancer in postmenopausal women with visceral and non-visceral metastases. Assessment was by means of a retrospective subgroup analysis of combined data from two randomised, phase III trials. Objective response (OR) rates were similar in patients treated with fulvestrant and anastrozole, respectively (21.9% versus 19.3%-patients with no visceral metastases; 15.7% versus 13.2%-all of the patients with visceral metastases; 18.8% versus 14.0%-patients with visceral metastases only). The proportion of patients with clinical benefit (CB) was also similar between treatments and between subgroups with and without visceral disease. Fulvestrant is at least as effective as anastrozole, providing a valuable treatment option for advanced breast cancer in postmenopausal women with visceral metastases who have failed on prior endocrine therapy.

Anastrozole↗
PubMed2003

Postmenopausal women who progress on fulvestrant ('Faslodex') remain sensitive to further endocrine therapy.

PURPOSE: This retrospective evaluation of data from two randomized, multicenter trials examined whether tumor responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who had progressed on both initial endocrine therapy, usually tamoxifen, and on the estrogen receptor (ER) antagonist fulvestrant ('Faslodex'). PATIENTS AND METHODS: A combined total of 423 patients received fulvestrant 250 mg as a monthly intramuscular injection. After progression on fulvestrant, some patients received another endocrine therapy. Responses to subsequent endocrine therapy were assessed using a questionnaire sent to the trial investigators. Best responses were classified as a complete or partial response (CR or PR), stable disease (SD) lasting > or = 24 weeks, or disease progression. RESULTS: Follow-up data were available for 54 patients who derived clinical benefit (CB, defined as CR, PR or SD) from fulvestrant and who received subsequent endocrine therapy, resulting in a PR in 4 patients, SD in 21 patients, and disease progression in 29 patients. Data were available for 51 patients who derived no CB from fulvestrant and who received further endocrine therapy, resulting in a PR in 1 patient, SD in 17 patients, and disease progression in 33 patients. Aromatase inhibitors were used as subsequent endocrine therapy in > 80% of patients. CONCLUSIONS: After progression on fulvestrant, patients may retain sensitivity to other endocrine agents. Fulvestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic breast cancer in postmenopausal women, and may provide the opportunity to extend the sequence of endocrine regimens before cytotoxic chemotherapy is required.

Adult↗
PubMed2002

Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment. PATIENTS AND METHODS: In this double-blind, double-dummy, parallel-group study, postmenopausal patients were randomized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rate, duration of response (DOR), and tolerability. RESULTS: Patients (n = 400) were followed for a median period of 16.8 months. Fulvestrant was as effective as anastrozole in terms of TTP (hazard ratio, 0.92; 95.14% confidence interval [CI], 0.74 to 1.14; P =.43); median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole. OR rates were 17.5% with both treatments. Clinical benefit rates (complete response + partial response + stable disease > or = 24 weeks) were 42.2% for fulvestrant and 36.1% for anastrozole (95% CI, -4.00% to 16.41%; P =.26). In responding patients, median DOR (from randomization to progression) was 19.0 months for fulvestrant and 10.8 months for anastrozole. Using all patients, DOR was significantly greater for fulvestrant compared with anastrozole; the ratio of average response durations was 1.35 (95% CI, 1.10 to 1.67; P < 0.01). Both treatments were well tolerated. CONCLUSION: Fulvestrant was at least as effective as anastrozole, with efficacy end points slightly favoring fulvestrant. Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy.

Adult↗
PubMed2001

Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth.

Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptor alpha (ERalpha) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ERalpha (C4 and C4-12 cells are ERalpha-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogen-mediated signaling and growth was a consequence of loss of ERalpha, we re-expressed ERalpha in C4-12 cells by stable transfection with HA-tagged ERalpha. Three independent C4-12 ERalpha-HA clones expressed a functional ERalpha that (a) was down-regulated by estrogen, (b) conferred estrogen-induction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERalpha-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERalpha-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERalpha is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERalpha expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line.

Breast Neoplasms↗
PubMed2001

Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions.

In a search for novel transcriptional intermediary factors for the estrogen receptor (ER), we used the ligand-binding domain and hinge region of ER as bait in a yeast two-hybrid screen of a cDNA library derived from tamoxifen-resistant MCF-7 human breast tumors from an in vivo athymic nude mouse model. Here we report the isolation and characterization of the forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the hepatocyte nuclear factor 3/forkhead homeotic gene family, as a nuclear hormone receptor (NR) intermediary protein. FKHR interacts with both steroid and nonsteroid NRs, although the effect of ligand on this interaction varies by receptor type. The interaction of FKHR with ER is enhanced by estrogen, whereas its interaction with thyroid hormone receptor and retinoic acid receptor is ligand-independent. In addition, FKHR differentially regulates the transactivation mediated by different NRs. Transient transfection of FKHR into mammalian cells dramatically represses transcription mediated by the ER, glucocorticoid receptor, and progesterone receptor. In contrast, FKHR stimulates rather than represses retinoic acid receptor- and thyroid hormone receptor-mediated transactivation. Most intriguingly, overexpression of FKHR dramatically inhibits the proliferation of ER-dependent MCF-7 breast cancer cells. Therefore, FKHR represents a bifunctional NR intermediary protein that can act as either a coactivator or corepressor, depending on the receptor type.

Amino Acid Sequence↗
PubMed2001

Loss of heterozygosity events impeding breast cancer metastasis contain the MTA1 gene.

Breast cancer mortality is seldom attributable to the primary tumor, but rather to the presence of systemic (metastatic) disease. Axillary lymph node dissection can identify the presence of metastatic breast cancer cells and serves as a marker for systemic disease. Previous work in our laboratory determined that rates of loss of heterozygosity (LOH) of a 1.6-Mb region of chromosome 14q 31.2 is much higher in axillary lymph node-negative primary breast tumors than in axillary lymph node-positive primary breast tumors (P. O'Connell et al., J. NATL: Cancer INST:, 91: 1391-1397, 1999.). This unusual observation suggests that, whereas the LOH of this region promotes primary breast cancer formation, some gene(s) mapping to this 1.6-Mb region is rate-limiting for breast cancer metastasis. Thus, if primary breast cancers delete this region, their ability to metastasize decreases. To identify this gene(s), we have physically mapped this area of chromosome 14q, confirmed the position of two known genes and 13 other expressed sequence tags into this 1.6-Mb region. One of these, the metastasis-associated 1 (MTA1) gene, previously identified as a metastasis-promoting gene (Y. Toh et al., J. BIOL: CHEM:, 269: 22958-22963, 1994.), mapped to the center of our 1.6-Mb target region. Thus, MTA1 represents a strong candidate for this breast cancer metastasis-promoting gene.

Breast Neoplasms↗
PubMed2001

Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition.

We hypothesize that elevation of Nm23-H1 expression in micrometastatic breast cancer cells may inhibit their metastatic colonization and further invasion, and induce differentiation, thus resulting in a clinical benefit. The current study investigated the possible contribution of DNA methylation to the regulation of Nm23-H1 expression, based on the observation that two CpG islands are present in its promoter. 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methylation inhibitor, increased the Nm23-H1 expression of 5 of 11 human breast carcinoma cell lines in vitro, including 3 of 3 metastatically competent lines. Increased Nm23-H1 expression was accompanied by a reduction in motility in vitro, with minimal effect on proliferation. Both increased Nm23-H1 expression and decreased motility were observed using low (75 nM) concentrations of 5-Aza-CdR. Array analysis of MDA-MB-231 breast carcinoma cells treated with 5-Aza-CdR confirmed the elevation of nm23-H1 mRNA, whereas relatively few other genes exhibited altered expression. Bisulfite sequencing of the two CpG islands in a panel of cell lines and in 20 infiltrating ductal carcinomas revealed that one island (-3090 bp to -3922 bp) exhibited infrequent differential methylation. The data indicate that DNA methylation inhibitors can directly or indirectly cause both elevation of Nm23-H1 expression and decreased function in one aspect of metastasis, motility.

Antimetabolites, Antineoplastic↗
PubMed2001

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer.

We have recently discovered that the nuclear matrix protein SAFB is an oestrogen receptor corepressor. Since it has become clear that many steroid receptor cofactors play important roles in breast tumorigenesis, we investigated whether SAFB could also be involved in breast cancer. To address this question, the gene locus was examined for structural alterations in breast cancer tissue. Laser capture microdissection was used for isolating DNA from paired primary breast tumour and normal tissue specimens, and the loss of heterozygosity (LOH) at chromosome 19p13.2-3 was determined by use of microsatellite markers. LOH was detected at the marker D19S216, which colocalizes with the SAFB locus, in specimens from 29 (78.4%) of 37 informative patients. The peak LOH rate occurred at D19S216 near the SAFB locus, with LOH frequencies ranging from 21.6% to 47.2% at other markers. The finding of a very high LOH rate at the marker D19S216 strongly indicates the presence of a breast tumour-suppressor gene locus. While preliminary findings of mutations in SAFB suggest that this indeed may be a promising candidate, other potential candidate genes are located at this locus.

Antigens, Nuclear↗
PubMed2001

Estrogen receptor: current understanding of its activation and modulation.

Breast cancer development and progression are directly related to the effects of the female hormone estrogen. The nuclear receptor for estrogen (ER) functions as a transcription factor controlling estrogen-regulated genes. Receptor conformation on ligand binding, its interaction with various coregulators, and response elements in the promoter region of target genes all contribute to the net estrogenic effects in a cell. ER is an important diagnostic and therapeutic target in breast cancer. Various polypeptide growth factors and their membrane receptors also contribute to breast cancer development and progression. Pathways mediating cell survival, cell proliferation, and response to stress not only generate signals through various protein kinase pathways to enhance cell survival and proliferation, but these pathways also interact with ERs. Kinases in the growth factor cascade can phosphorylate and activate ER, and ER in turn activates and augments signaling through the growth factor pathways. Signaling through the growth factor pathways may contribute to hormonal resistance states by ligand-independent activation of ER. Targeting growth factor pathways, in addition to ER, is a developing strategy that hypothetically may represent optimal therapy by preventing the development of resistance to endocrine therapy.

Animals↗
PubMed2000

Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo.

BACKGROUND: Most breast cancers, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumor growth by tamoxifen, is unclear. Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signaling pathways leading to the activation of activating protein-1 (AP-1), we investigated whether tamoxifen-resistant growth in vivo is associated with oxidative stress and/or activation of AP-1 in a xenograft model system where resistance is caused by tamoxifen-stimulated growth. METHODS: Control estrogen-treated, tamoxifen-sensitive, and tamoxifen-resistant MCF-7 xenograft tumors were assessed for oxidative stress by measuring levels of antioxidant enzyme (e.g., superoxide dismutase [SOD], glutathione S-transferase [GST], and hexose monophosphate shunt [HMS]) activity, glutathione, and lipid peroxidation. AP-1 protein levels, phosphorylated c-jun levels, and phosphorylated Jun NH(2)-terminal kinase (JNK) levels were examined by western blot analyses, and AP-1 DNA-binding and transcriptional activities were assessed by electrophoretic mobility shift assays and a reporter gene system. All statistical tests are two-sided. RESULTS: Compared with control estrogen-treated tumors, tamoxifen resistant tumors had statistically significantly increased SOD (more than threefold; P=.004) and GST (twofold; P=.004) activity and statistically significantly reduced glutathione levels (greater than twofold; P<.001) and HMS activity (10-fold; P<.001). Lipid peroxides were not significantly different between control and tamoxifen-resistant tumors. We observed no differences in AP-1 protein components or DNA-binding activity. However, AP-1-dependent transcription (P=.04) and phosphorylated c-Jun and JNK levels (P<.001) were statistically significantly increased in the tamoxifen-resistant tumors. CONCLUSION: Our results suggest that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and the subsequent antioxidant response and with increased phosphorylated JNK and c-Jun levels and AP-1 activity, which together could contribute to tumor growth.

Animals↗
PubMed2000

ICI 182,780 (Faslodex): development of a novel, "pure" antiestrogen.

BACKGROUND: The nonsteroidal antiestrogen tamoxifen is well established as an effective treatment for patients with breast carcinoma, both for the treatment of metastatic disease and as an adjuvant to surgery for patients with primary breast carcinoma. In addition to exerting antagonistic effects on the estrogen receptor, tamoxifen and its derivatives act as partial agonists on certain tissues. These agonistic effects, for example, endometrial stimulation and stimulation of tumor growth after previous response to tamoxifen, may limit their clinical efficacy. ICI 182,780 (Faslodex) from AstraZeneca (Cheshire, United Kingdom) is a novel, steroidal estrogen antagonist that was designed to be devoid of estrogen agonist activity in preclinical models. METHODS: ICI 182,780 was tested in a large number of in vitro and in vivo preclinical models, and its value was assessed clinically when administered before surgery for breast carcinoma and hysterectomy for benign conditions and after failure of tamoxifen in patients with advanced breast carcinoma. RESULTS: All data indicated that ICI 182,780 is devoid of agonist activity in preclinical models and in clinical trials. It inhibits growth of the breast and endometrium. In animal models, it does not cross the blood-brain barrier and appears to be neutral with respect to lipids and bone. ICI 182,780 down-regulates the estrogen receptor and is active in tamoxifen-resistant breast carcinoma. In a small, Phase II study, durable responses were seen: Phase III clinical trials are in progress comparing ICI 182,780 with anastrozole and tamoxifen in the treatment of patients with advanced breast carcinoma. CONCLUSIONS: ICI 182,780 specifically down-regulates the estrogen receptor and, thus, represents the first of a new class of therapeutic agents. In this report, the authors present the current evidence that distinguishes ICI 182,780 from tamoxifen and related nonsteroidal compounds and establishes ICI 182,780 as the first in a new class of therapeutic agents.

Animals↗
PubMed2000

Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study.

Results of estrogen receptor (ER) and progesterone receptor (PgR) ligand-binding assays (LBAs) are strongly correlated with ER and PgR by immuno-histochemistry (IHC). To investigate whether ER and PgR by IHC are also strongly correlated with tamoxifen response, time to treatment failure (TTF) and overall survival (OS), the results of the 2 methods were directly compared in 205 patients with ER(+) metastatic breast cancer treated with daily tamoxifen (Southwest Oncology Group protocol 8228) with 9 years median follow-up. pS2, another estrogen-regulated molecule, was also analyzed. Tumors were scored for IHC from 0 to 5, according to the proportion of positively stained cells. These IHC scores for both ER and PgR were significantly associated with LBA levels (p < 0.001). There was a significant direct relationship between higher IHC ER, PgR and pS2 and increasing response to tamoxifen. TTF and OS were also significantly longer for patients with higher ER or PgR, but not pS2, IHC scores. Low, intermediate and high ER or PgR categories showed similar differences in response rates whether defined by LBA or IHC. In logistic regression models which included ER, PgR and pS2 by IHC; ER and PgR by LBA; and menopausal status, only ER (IHC) and pS2 (IHC) retained significance for predicting tamoxifen response (p = 0. 02 and p = 0.005, respectively), along with menopausal status (for PgR by IHC, p = 0.09). Increasing ER and PgR by IHC, as by LBA, are thus significantly associated with a progressively better response and longer survival in ER(+) metastatic breast cancer. pS2 is also predictive in this setting.

Antineoplastic Agents, Hormonal↗
PubMed2000

Selective estrogen receptor modulators: structure, function, and clinical use.

The sex hormone estrogen is important for many physiologic processes. Prolonged stimulation of breast ductal epithelium by estrogen, however, can contribute to the development and progression of breast cancer, and treatments designed to block estrogen's effects are important options in the clinic. Tamoxifen and other similar drugs are effective in breast cancer prevention and treatment by inhibiting the proliferative effects of estrogen that are mediated through the estrogen receptor (ER). However, these drugs also have many estrogenic effects depending on the tissue and gene, and they are more appropriately called selective estrogen receptor modulators (SERMs). SERMs bind ER, alter receptor conformation, and facilitate binding of coregulatory proteins that activate or repress transcriptional activation of estrogen target genes. Theoretically, SERMs could be synthesized that would exhibit nearly complete agonist activity on the one hand or pure antiestrogenic activity on the other. Depending on their functional activities, SERMs could then be developed for a variety of clinical uses, including prevention and treatment of osteoporosis, treatment and prevention of estrogen-regulated malignancies, and even for hormone replacement therapy. Tamoxifen is effective in patients with ER-positive metastatic breast cancer and in the adjuvant setting. The promising role for tamoxifen in ductal carcinoma-in-situ or for breast cancer prevention is evolving, and its use can be considered in certain patient groups. Other SERMs are in development, with the goal of reducing toxicity and/or improving efficacy, and future agents have the potential of providing a new paradigm for maintaining the health of women.

Animals↗
PubMed2000

Tamoxifen-bound estrogen receptor (ER) strongly interacts with the nuclear matrix protein HET/SAF-B, a novel inhibitor of ER-mediated transactivation.

The estrogen receptor (ER) is a ligand-dependent transcription factor that acts in a cell- and promoter-specific manner. Evidence suggests that the activity of the ER can be regulated by a number of other stimuli (e.g. growth factors) and that the effects of the ER are modulated by nuclear factors termed coregulators. While the interplay among these factors may in part explain the pleiotropic effects elicited by the ER, there are several other less well described mechanisms of control, such as interactions with the nuclear matrix. Here we report that the nuclear matrix protein/scaffold attachment factor HET/SAF-B is an ER-interacting protein. ER and HET/SAF-B interact in in vitro binding assays, with HET binding to both the ER DNA-binding domain and the hinge region. Coimmunoprecipitation experiments reveal that HET/SAF-B and ER associate in cell lines in the presence or absence of estradiol, but binding is increased by the antiestrogen tamoxifen. HET/SAF-B enhances tamoxifen antagonism of estrogen-induced ER-mediated transactivation, but at high concentrations can inhibit both estrogen and tamoxifen-induced ER activity. HET/SAF-B-mediated repression of ER activity is dependent upon interaction with the ER-DBD. While the existence of high-affinity binding sites for the ER in the nuclear matrix has been known for some time, we now provide evidence of a specific nuclear matrix protein binding to the ER. Furthermore, our data showing that HET/SAF-B binds to ER particularly strongly in the presence of tamoxifen suggests that it may be important for the antagonist effect of tamoxifen.

Adenocarcinoma↗
PubMed2000

Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients.

The aim of this study was to evaluate pretreatment clinical features and biological markers together with changes in these factors as predictors of response and relapse in patients receiving tamoxifen for primary breast cancer. Fine-needle aspiration cytology of the primary breast cancer was performed before tamoxifen treatment in 54 patients and repeated after therapy on day 14, day 60, or on both days in a subset of 35 patients. These samples were evaluated for estrogen receptor (ER), progesterone receptor (PgR), Ki67, S-phase fraction and ploidy. The overall response to tamoxifen was 57% (31 of 54 patients). Pretreatment ER and PgR significantly predicted for response by univariate analysis (P < 0.0001 and P < 0.003, respectively). By multivariate analysis, ER expression was the only independent predictor of response, and it was associated with 27 times the likelihood of response (95% confidence interval, 6-136). Increase in PgR and decrease in Ki67 on day 14 significantly predicted for response to tamoxifen (P < 0.03 and P < 0.04, respectively). Lack of ER, clinical node-positive disease, and failure to decrease Ki67 on day 14 were significantly associated with increased risk of relapse (P < 0.05). By multivariate analysis, ER expression was the only independent predictor of relapse (P < 0.005). Pretreatment and early changes in molecular marker expression may assist in the prediction of response and clinical outcome in primary breast cancer patients receiving tamoxifen.

Aged↗
PubMed2000

HET/SAF-B overexpression causes growth arrest and multinuclearity and is associated with aneuploidy in human breast cancer.

HET/SAF-B was originally cloned as a nuclear matrix protein that bound to matrix attachment regions and as a transcriptional repressor of the small heat shock protein hsp27. In addition, we have found recently that HET/SAF-B is also a corepressor of estrogen receptor activity. Estrogen receptor has a very well-described role in breast cancer, and aberrant expression of nuclear matrix and heat shock proteins has also been implicated in breast tumorigenesis. Therefore, we asked whether HET/SAF-B itself could be important in breast cancer. Toward this goal we examined its expression in breast cancer cell lines and asked whether HET/SAF-B can affect breast cancer cell proliferation. Finally, we studied HET/SAF-B expression in clinical breast cancer samples. HET/SAF-B protein and mRNA were detected at varying levels in all of the eight breast cancer cell lines examined. Using a number of different approaches to modulate the level of HET/SAF-B protein in the cell, we found that HET/SAF-B levels are inversely correlated with cell proliferation. In addition,transfection of HET/SAF-B fused to the green fluorescent protein led to the formation of multinucleated cells not observed in cells transfected with green fluorescent protein alone, suggesting that this effect is a direct result of HET/SAF-B overexpression. Western blot analysis of HET/SAF-B in 61 human breast tumors revealed widely varying levels of HET/SAF-B expression, with some tumors (16%) lacking any detectable HET/SAF-B. Statistical analysis showed that high HET/SAF-B expression in these tumors was associated with low S-phase fraction and with aneuploidy, consistent with our results from transfection experiments in tissue culture cells. We conclude that HET/SAF-B plays an important role in breast cancer, and we discuss possible mechanisms of the involvement of HET/SAF-B in cell proliferation and division.

3T3 Cells↗
PubMed1999

Loss of heterozygosity at D14S62 and metastatic potential of breast cancer.

BACKGROUND: In breast cancer progression, the prevalence of damage at specific genetic loci often increases with the stage of the lesion (i.e., from noninvasive to invasive to metastatic). By use of genetic markers and analysis of allelic imbalances (loss of heterozygosity [LOH]) to compare DNA samples from paired normal and breast tumor tissues, we examined whether specific genetic changes in primary breast cancers can serve as biomarkers of metastatic potential. METHODS: DNA samples from 76 patients with primary breast cancer (42 with axillary lymph node-negative disease and 34 with axillary lymph node-positive disease) were genotyped with four genetic markers spanning chromosome 14q31-q32. The intensity ratios of the two genetic alleles in normal-tumor DNA pairs were examined in genetically informative individuals. LOH was scored when the tumor allele intensity ratio (tumor allele 1/tumor allele 2) divided by the normal allele intensity ratio (normal allele 1/normal allele 2) was either less than 0.71 (tumor allele 1 LOH) or greater than 1. 4 (tumor allele 2 LOH). RESULTS/CONCLUSIONS: Contrary to our expectations, we found statistically significantly more LOH events at markers D14S62 (two-sided P =.001) and D14S51 (two-sided P =.02) in primary breast cancers from patients with lymph node-negative disease versus lymph node-positive disease, suggesting the presence of a gene in this region that affects metastatic potential. Analysis of small interstitial or terminal deletions in the tumors of six especially informative patients with lymph node-negative disease places the putative metastasis-related gene in a 1490-kilobase region near D14S62. IMPLICATIONS: LOH in the D14S62 region may impede the process of metastasis. Therefore, the D14S62 region LOH profile may have prognostic implications, and the isolation of the metastasis-related gene(s) in this region may lead to better diagnosis and treatment of breast cancer.

Biomarkers, Tumor↗