Biomedical subjects

Alexander Miron

Publications and source records attributed to Alexander Miron.

13 recordsLinked to original sources

PubMed2007

BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays.

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

Adult↗

PubMed2007

The distal fallopian tube: a new model for pelvic serous carcinogenesis.

PURPOSE OF REVIEW: Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, remove or prevent the earliest stages of the most lethal form of ovarian cancer. RECENT FINDINGS: The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the 'p53 signature', suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa. SUMMARY: A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of 'fimbrial-ovarian' serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.

Adenocarcinoma, Mucinous↗

PubMed2006

Rapamycin inhibits proliferation of estrogen-receptor-positive breast cancer cells.

BACKGROUND: Estrogen-receptor (ER)-positive breast cancers comprise the majority of sporadic breast cancers. Although 50% respond to antihormonal treatment, both primary and acquired resistance limit the utility of this therapy, and other agents are needed. Rapamycin, an inhibitor of the mammalian Target of Rapamycin (mTOR), possesses antitumor activity against many tumors including breast tumors, and particularly against ER-positive breast cancer cell lines. The sensitivity of these cells to rapamycin has been attributed to activation of the PI3K/Akt/mTOR pathway by nongenomic ER signaling. The purpose of this study was to evaluate the efficacy of rapamycin against ER-positive breast cancer, particularly under 17beta-estradiol (E2)-dependent conditions, and to investigate mechanisms of rapamycin-sensitivity in ER-positive cells. MATERIALS AND METHODS: Breast cancer cell lines were tested for sensitivity to rapamycin. Antiproliferative effects of rapamycin, alone and in combination with tamoxifen, were assessed under E2-dependent conditions. Western blot analysis was used to detect activation of mTOR by nongenomic ER signaling. RESULTS: Rapamycin effectively inhibits proliferation of the ER-positive MCF-7 cell line. In our system, this sensitivity is probably not due to nongenomic ER activation of the PI3K/Akt/mTOR pathway; rapid stimulation of mTOR occurred nonspecifically after medium replacement, and addition of E2 stimulated mTOR only after 1 h. Combining rapamycin and tamoxifen under E2-dependent conditions yielded additive/synergistic effects at effective concentrations. CONCLUSIONS: These results suggest that rapamycin may be an effective treatment for ER-positive breast cancer, either alone or in combination with tamoxifen, and also may be a potential therapy for tamoxifen-resistant cancers.

Antibiotics, Antineoplastic↗

PubMed2006

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

Adult↗

PubMed2006

Recursive SVM feature selection and sample classification for mass-spectrometry and microarray data.

BACKGROUND: Like microarray-based investigations, high-throughput proteomics techniques require machine learning algorithms to identify biomarkers that are informative for biological classification problems. Feature selection and classification algorithms need to be robust to noise and outliers in the data. RESULTS: We developed a recursive support vector machine (R-SVM) algorithm to select important genes/biomarkers for the classification of noisy data. We compared its performance to a similar, state-of-the-art method (SVM recursive feature elimination or SVM-RFE), paying special attention to the ability of recovering the true informative genes/biomarkers and the robustness to outliers in the data. Simulation experiments show that a 5%- approximately 20% improvement over SVM-RFE can be achieved regard to these properties. The SVM-based methods are also compared with a conventional univariate method and their respective strengths and weaknesses are discussed. R-SVM was applied to two sets of SELDI-TOF-MS proteomics data, one from a human breast cancer study and the other from a study on rat liver cirrhosis. Important biomarkers found by the algorithm were validated by follow-up biological experiments. CONCLUSION: The proposed R-SVM method is suitable for analyzing noisy high-throughput proteomics and microarray data and it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features. The multivariate SVM-based method outperforms the univariate method in the classification performance, but univariate methods can reveal more of the differentially expressed features especially when there are correlations between the features.

Algorithms↗

PubMed2006

X chromosomal abnormalities in basal-like human breast cancer.

Sporadic basal-like cancers (BLC) are a distinct class of human breast cancers that are phenotypically similar to BRCA1-associated cancers. Like BRCA1-deficient tumors, most BLC lack markers of a normal inactive X chromosome (Xi). Duplication of the active X chromosome and loss of Xi characterized almost half of BLC cases tested. Others contained biparental but nonheterochromatinized X chromosomes or gains of X chromosomal DNA. These abnormalities did not lead to a global increase in X chromosome transcription but were associated with overexpression of a small subset of X chromosomal genes. Other, equally aneuploid, but non-BLC rarely displayed these X chromosome abnormalities. These results suggest that X chromosome abnormalities contribute to the pathogenesis of BLC, both inherited and sporadic.

Alleles↗

PubMed2006

Declining plasma fibrinogen alpha fragment identifies HER2-positive breast cancer patients and reverts to normal levels after surgery.

Breast cancer is the most common nonskin malignancy affecting women. Currently, no simple, blood-based diagnostic test exists to complement radiological screening and increase sensitivity of detection. To screen plasma specimens and identify biomarkers that detect HER2-positive breast cancer, automated robotic sample processing followed by surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) mass spectroscopy was used. Multiple statistical algorithms were used to select biomarkers that segregate cancer patients versus controls and produced average CV rates ranging from 20% to 29%. A set of seven biomarkers were validated on an independent test data set and achieved the best error rate of 19.1%. A permutation test indicated a p-value for CV error less than 0.002. Moreover, a ROC curve using these biomarkers achieved an area-under-the-curve value of 0.95 on an independent test data set. The marker responsible for most of the resolving power was identified as a fragment of Fibrinogen Alpha (FGA) encompassing residues 605-629. This marker was present at lower levels in cancer patients as compared to controls. The importance of this biomarker was validated in a longitudinal study comparing pre- and post-operative levels and was shown to revert to normal levels after surgery. This fragment may serve as a useful diagnostic and treatment-monitoring marker.

Amino Acid Sequence↗

PubMed2006

Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations.

BACKGROUND: First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis. METHODS: We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis. RESULTS: In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years. CONCLUSION: In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

Adult↗

PubMed2006

The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers.

This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Acetyltransferases↗

PubMed2006

Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342.

INTRODUCTION: The response to paclitaxel varies widely in metastatic breast cancer. We analyzed data from CALGB 9342, which tested three doses of paclitaxel in women with advanced disease, to determine whether response and outcomes differed according to HER2, hormone receptor, and p53 status. METHODS: Among 474 women randomly assigned to paclitaxel at a dose of 175, 210, or 250 mg/m2, adequate primary tumor tissue was available from 175. Immunohistochemistry with two antibodies and fluorescence in situ hybridization were performed to evaluate HER2 status; p53 status was determined by immunohistochemistry and sequencing. Hormone receptor status was obtained from pathology reports. RESULTS: Objective response rate was not associated with HER2 or p53 status. There was a trend toward a shorter median time to treatment failure among women with HER2-positive tumors (2.3 versus 4.2 months; P = 0.067). HER2 status was not related to overall survival (OS). Hormone receptor expression was not associated with differences in response but was associated with longer OS (P = 0.003). In contrast, women with p53 over-expression had significantly shorter OS than those without p53 over-expression (11.5 versus 14.4 months; P = 0.002). In addition, triple negative tumors were more frequent in African-American than in Caucasian patients, and were associated with a significant reduction in OS (8.7 versus 12.9 months; P = 0.008). CONCLUSION: None of the biomarkers was predictive of treatment response in women with metastatic breast cancer; however, survival differed according to hormone receptor and p53 status. Triple negative tumors were more frequent in African-American patients and were associated with a shorter survival.

Black or African American↗

PubMed2005

BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles.

BRCA1 is a tumor suppressor gene that functions in DNA repair. Basal-like tumors are a distinctive subtype of breast cancer defined by gene expression profiles. Hereditary BRCA1 breast tumors and basal-like sporadic tumors have a similar phenotype and gene expression signature, suggesting involvement of BRCA1 in the pathogenesis of sporadic basal-like cancer. This study evaluates the role of BRCA1 in sporadic breast tumorigenesis. BRCA1 protein expression and promoter methylation are compared to tumor histopathology and gene expression profiles. We find BRCA1 protein expression correlates with tumor mitotic rate, consistent with normal cell-cycle regulation of the BRCA1 gene. Methylation is found in 21% of tumors and is associated with lower BRCA1 protein, but not with specific pathologic features. Basal-like tumors, defined by hierarchical clustering of gene expression, have infrequent BRCA1 methylation and high levels of BRCA1 protein expression consistent with their high mitotic rate. Tumors with BRCA1 promoter methylation are present in all expression clusters; however, a subgroup of ER-positive high-grade tumors has a significantly greater number of BRCA1 methylated tumors. Absence of BRCA1 promoter methylation and high levels of BRCA1 expression in basal-like sporadic tumors suggest alternate explanations for the phenotypic similarities of these tumors to hereditary BRCA1 tumors.

Breast Neoplasms↗

PubMed2004

Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers.

Gene expression array profiles identify subclasses of breast cancers with different clinical outcomes and different molecular features. The present study attempted to correlate genomic alterations (loss of heterozygosity; LOH) with subclasses of breast cancers having distinct gene expression signatures. Hierarchical clustering of expression array data from 89 invasive breast cancers identified four major expression subclasses. Thirty-four of these cases representative of the four subclasses were microdissected and allelotyped using genome-wide single nucleotide polymorphism detection arrays (Affymetrix, Inc.). LOH was determined by comparing tumor and normal single nucleotide polymorphism allelotypes. A newly developed statistical tool was used to determine the chromosomal regions of frequent LOH. We found that breast cancers were highly heterogeneous, with the proportion of LOH ranging widely from 0.3% to >60% of heterozygous markers. The most common sites of LOH were on 17p, 17q, 16q, 11q, and 14q, sites reported in previous LOH studies. Signature LOH events were discovered in certain expression subclasses. Unique regions of LOH on 5q and 4p marked a subclass of breast cancers with "basal-like" expression profiles, distinct from other subclasses. LOH on 1p and 16q occurred preferentially in a subclass of estrogen receptor-positive breast cancers. Finding unique LOH patterns in different groups of breast cancer, in part defined by expression signatures, adds confidence to newer schemes of molecular classification. Furthermore, exclusive association between biological subclasses and restricted LOH events provides rationale to search for targeted genes.

Breast Neoplasms↗

PubMed2002

BRCA1 supports XIST RNA concentration on the inactive X chromosome.

BRCA1, a breast and ovarian tumor suppressor, colocalizes with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associates with XIST RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 show evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wt BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggest that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state.

Animals↗