Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.

We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells. BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells. These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression.

Growth retardation and tumour inhibition by BRCA1.

Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the role of BRCA1 in sporadic breast and ovarian cancer has previously been elusive. Here, we show that retroviral transfer of the wild-type BRCA1 gene inhibits growth in vitro of all breast and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1 has no effect on growth of breast cancer cells; ovarian cancer cell growth is not affected by BRCA1 mutations in the 5' portion of the gene, but is inhibited by 3' BRCA1 mutations. Development of MCF-7 tumours in nude mice is inhibited when MCF-7 cells are transfected with wild-type, but not mutant, BRCA1. Most importantly, among mice with established MCF-7 tumours, peritoneal treatment with a retroviral vector expressing wild-type BRCA1 significantly inhibits tumour growth and increased survival.

BRCA1 is secreted and exhibits properties of a granin.

Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer. However, the function of the BRCA1 protein has remained elusive. We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones. As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products.

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

Genetic dissection reveals diabetes loci proximal to the gimap5 lymphopenia gene.

Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped and monitored for T1D, and positional candidate genes were sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (region 1) resulted in 47% protection and significantly delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (region 2) resulted in 28% protection and also delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 region 1 interval to approximately 670 kb and region 2 to the 340 kb proximal to gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels, but <20% of islets in nondiabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12, and 13 as candidate genes in region 1 and znf467 and atp6v0e2 as candidate genes in region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4.

Disease resistance: incorporation into sexually incompatible somatic hybrids of the genus Nicotiana.

Somatic hybrid plants of Nicotiana nesophila and N. stocktonii with N. tabacum (cultivated tobacco) were produced by protoplast fusion. These combinations cannot be achieved with conventional sexual hybridization, yet are important in that the wild Nicotiana species are resistant to numerous diseases. Hybridity was verified by chromosome number, isoenzyme analysis, morphological characteristics, and genetic behavior. Local lesion-type resistance to tobacco mosaic virus has been observed in leaves of these somatic hybrid plants.

New insights into regulation of the tryptophan biosynthetic operon in Gram-positive bacteria.

The tryptophan operon of Bacillus subtilis serves as an excellent model for investigating transcription regulation in Gram-positive bacteria. In this article, we extend this knowledge by analyzing the predicted regulatory regions in the trp operons of other fully sequenced Gram-positive bacteria. Interestingly, it appears that in eight of the organisms examined, transcription of the trp operon appears to be regulated by tandem T-box elements. These regulatory elements have recently been described in the trp operons of two bacterial species. Single T-box elements are commonly found in Gram-positive bacteria in operons encoding aminoacyl tRNA synthetases and proteins performing other functions. Different regulatory mechanisms appear to be associated with variations of trp gene organization within the trp operon.

Enhanced recognition memory following vagus nerve stimulation in human subjects.

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

L-type cardiac calcium channels in doxorubicin cardiomyopathy in rats morphological, biochemical, and functional correlations.

Doxorubicin (DXR) is an effective antitumor agent in a wide spectrum of neoplasms. Chronic treatment is associated with cardiomyopathy and characteristic myocardial ultrastructural changes, which include swelling of the t tubules. Accordingly, we investigated excitation-contraction coupling in cardiomyopathic rat heart resulting from chronic DXR treatment. Using the whole-cell patch clamp technique, we studied the L-type calcium channel in single cells enzymatically isolated from normal (CTRL) and DXR rat hearts. Despite similar cell dimensions, the total membrane capacitance was significantly smaller in the DXR cells (138 +/- 9 pF) than in the CTRL cells (169 +/- 11 pF) (mean +/- SEM, n = 9, P less than 0.05). The mean current and the current density-voltage relationships of the CTRL and the DXR cells were significantly different (n = 9, P less than 0.001) with the maximal peak L-type calcium current (ICa) density increased from 6.4 +/- 0.9 in CTRL cells to 10.5 +/- 2.4 microA/cm2 in the DXR cells (P less than 0.05). There was no shift either in the current-voltage relationship or the steady-state inactivation curve in the two cell groups. However, the fast time constant of inactivation was increased at a membrane voltage of -10 to 10 mV. Calcium channel antagonist equilibrium binding assays using [3H]-PN200-110 revealed no difference in the maximal receptor binding capacity (CTRL, 194 +/- 27 and DXR 211 +/- 24 fmol/mg protein; P greater than 0.05, n = 6) and in receptor affinity (CTRL, 0.15 +/- 0.05 and DXR 0.13 +/- 0.03 nM; P less than 0.05). These data suggest that a decrease in effective capacitance might be associated with t-tubular damage. Despite this decrease, ICa was increased in the DXR cells. Such an increase may result from an alteration in the properties of the calcium channels and/or recruitment of "hibernating" channels in the remaining surface and t-tubular membranes.

The aromatic amino acid pathway branches at L-arogenate in Euglena gracilis.

The recently characterized amino acid L-arogenate (Zamir et al., J. Am. Chem. Soc. 102:4499-4504, 1980) may be a precursor of either L-phenylalanine or L-tyrosine in nature. Euglena gracilis is the first example of an organism that uses L-arogenate as the sole precursor of both L-tyrosine and L-phenylalanine, thereby creating a pathway in which L-arogenate rather than prephenate becomes the metabolic branch point. E. gracilis ATCC 12796 was cultured in the light under myxotrophic conditions and harvested in late exponential phase before extract preparation for enzymological assays. Arogenate dehydrogenase was dependent upon nicotinamide adenine dinucleotide phosphate for activity. L-Tyrosine inhibited activity effectively with kinetics that were competitive with respect to L-arogenate and noncompetitive with respect to nicotinamide adenine dinucleotide phosphate. The possible inhibition of arogenate dehydratase by L-phenylalanine has not yet been determined. Beyond the latter uncertainty, the overall regulation of aromatic biosynthesis was studied through the characterization of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase and chorismate mutase. 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase was subject to noncompetitive inhibition by L-tyrosine with respect to either of the two substrates. Chorismate mutase was feedback inhibited with equal effectiveness by either L-tyrosine or L-phenylalanine. L-Tryptophan activated activity of chorismate mutase, a pH-dependent effect in which increased activation was dramatic above pH 7.8 L-Arogenate did not affect activity of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase or of chorismate mutase. Four species of prephenate aminotransferase activity were separated after ion-exchange chromatography. One aminotransferase exhibited a narrow range of substrate specificity, recognizing only the combination of L-glutamate with prephenate, phenylpyruvate, or 4-hydroxyphenylpyruvate. Possible natural relationships between Euglena spp. and fungi previously considered in the literature are discussed in terms of data currently available to define enzymological variation in the shikimate pathway.

Electrocardiographic and transmembrane potential effects of 5-iminodaunorubicin in the rat.

5-Iminodaunorubicin (5-ID) is a quinone-modified anthracycline that retains antitumor activity but lacks the usual redox-cycling effects of quinoid agents. As a test for decreased cardiotoxicity, we have compared the dose- and time-dependent effects of multiple doses of 5-ID and doxorubicin (DXR) on the rat electrocardiogram (ECG) using a signal-averaging process and have related the ECG changes induced by 5-ID to transmembrane potential alterations in myocardial preparations isolated from treated rats. 5-ID was studied at dose levels of 16, 4, and 1 mg/kg, while DXR was given at 4, 2, and 1 mg/kg. At the high- and medium-dose levels, both agents produced widening of the QRS complex, increased R- and S-wave voltage, and prolonged the Q alpha T interval. The QRS widening reversed in all surviving rats, whereas Q alpha T prolongation was reversible with 5-ID but irreversible with DXR. At the lowest dose, 5-ID had no effect on the ECG until the end of treatment. Microelectrode studies on single cells showed that QRS widening occurring with 5-ID treatment was related to a decrease in the maximum rate of depolarization (Vmax) and that Q alpha T prolongation resulted from an increase in the duration of the action potential. Electron microscopic examination showed that although these toxic changes could not be related to specific morphological alterations, in general, the more severe the electrophysiological change, the greater the ultrastructural change. The most consistent ECG change was Q alpha T prolongation. Using this parameter as a marker for cardiotoxicity, 5-ID was about 4 to 5 times less cardiotoxic than was DXR at high- and medium-dose levels and was noncardiotoxic (i.e., below a threshold for cardiotoxicity) compared with DXR at 1 mg/kg over 20 (DXR) to 35 (5-ID) treatments. The decrease in cardiotoxicity relative to DXR is consistent with previous findings that quinone redox cycling is suppressed in 5-ID. However, the ECG and transmembrane potential effects that we identified at elevated doses of 5-ID can be associated with toxic changes in cardiac cell membranes. Therefore, membrane changes other than those due to quinone redox cycling and, presumably, lipid peroxidation must underlie the electrophysiological changes and structural modifications observed with 5-ID in this study. We believe that 5-ID is a useful mechanistic probe in anthracycline cardiotoxicity studies as well as being of obvious interest for clinical trials.

Identification of ArgBP1, an Arg protein tyrosine kinase binding protein that is the human homologue of a CNS-specific Xenopus gene.

Arg and c-Abl represent the mammalian members of the Abelson family of nonreceptor protein-tyrosine kinases. To gain insight into the biological role of Arg we used the two-hybrid approach to identify interacting proteins. Using a C-terminal segment of Arg we identified a novel protein, ArgBP1 (Arg binding protein 1). ArgBP1 contains a C-terminal SH3 domain, several PEST sequences, a serine rich domain and an SH3 binding site. ArgBP1 is ubiquitously expressed as two transcripts of approximately 2.2 kb and approximately 8 kb with highest levels in brain, heart and testis. The association of ArgBP1 with Arg in living cells was confirmed by coimmunoprecipitation in cotransfected COS cells. Analysis of the mechanism of association indicated that the ArgBP1 SH3 domain binds to a C-terminal Arg SH3-binding site, and that an N-terminal ArgBP1 proline-rich sequence binds to the Arg SH3 domain. Immunostaining indicated that the subcellular localization of ArgBP1 is cytoplasmic. The similarity of the ArgBP1 expression pattern and subcellular localization to those of Arg and the potential for a highly specific and potentially strong association mediated by two pairs of SH3 domain/proline-rich motif interactions, suggest that ArgBP1 is likely to be a regulator and/or effector of Arg function.

The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.

NIH sponsored a meeting of medical and veterinary pathologists with mammary gland expertise in Annapolis in March 1999. Rapid development of mouse mammary models has accentuated the need for definitions of the mammary lesions in genetically engineered mice (GEM) and to assess their usefulness as models of human breast disease. The panel of nine pathologists independently reviewed material representing over 90% of the published systems. The GEM tumors were found to have: (1) phenotypes similar to those of non-GEM; (2) signature phenotypes specific to the transgene; and (3) some morphological similarities to the human disease. The current mouse mammary and human breast tumor classifications describe the majority of GEM lesions but unique morphologic lesions are found in many GEM. Since little information is available on the natural history of GEM lesions, a simple morphologic nomenclature is proposed that allows direct comparisons between models. Future progress requires rigorous application of guidelines covering pathologic examination of the mammary gland and the whole animal. Since the phenotype of the lesions is an essential component of their molecular pathology, funding agencies should adopt policies ensuring careful morphological evaluation of any funded research involving animal models. A pathologist should be part of each research team.

A phase I trial of retroviral BRCA1sv gene therapy in ovarian cancer.

Gene transfer of BRCA1sv (a normal splice variant of BRCA1) into ovarian cancer cells produces growth inhibition in vitro and tumor suppression in nude mouse xenografts. As an initial step toward gene replacement therapy for ovarian cancer, we conducted a Phase I trial to assess the pharmacokinetics and toxicity of i.p. BRCA1sv retroviral vector therapy. Following placement of an indwelling Port-a-Cath in patients, a dose escalation study was performed of four daily i.p. infusions spanning doses from 3 to 300 ml (i.e., 10(10) viral particles) at half-log intervals (23 cycles in 12 patients). Gene transfer and expression were documented by PCR, Southern blot, reverse transcription-PCR, and nuclease protection assays. Pharmacokinetics were assessed by PCR and Southern blots detecting vector DNA, and toxicity was evaluated by clinical exam and fluid analysis. Three of 12 patients developed an acute sterile peritonitis, which spontaneously resolved within 48 h. Plasma and peritoneal antibodies to the retroviral envelope protein were detected only in patients treated with the highest dose levels but not in others, despite repeat dosing for an interval of up to 4 months. Eight patients showed stable disease for 4-16 weeks, and three patients showed tumor reduction with diminished miliary tumor implants at reoperation (two patients) and radiographic shrinkage of measurable disease (one patient). The vector-related complication of peritonitis was observed in three patients but resolved quickly as in preclinical mouse studies. Ovarian cancer may provide an important model for retroviral gene therapy studies due to vector stability, minimal antibody response, and access to tumor by i.p. therapy.

High-mobility group (HMG) protein HMG-1 and TATA-binding protein-associated factor TAF(II)30 affect estrogen receptor-mediated transcriptional activation.

The estrogen receptor (ER) belongs to a family of ligand-inducible nuclear receptors that exert their effects by binding to cis-acting DNA elements in the regulatory region of target genes. The detailed mechanisms by which ER interacts with the estrogen response element (ERE) and affects transcription still remain to be elucidated. To study the ER-ERE interaction and transcription initiation, we employed purified recombinant ER expressed in both the baculovirus-Sf9 and his-tagged bacterial systems. The effect of high-mobility group (HMG) protein HMG-1 and purified recombinant TATA-binding protein-associated factor TAF(II)30 on ER-ERE binding and transcription initiation were assessed by electrophoretic mobility shift assay and in vitro transcription from an ERE-containing template (pERE2LovTATA), respectively. We find that purified, recombinant ER fails to bind to ERE in spite of high ligand-binding activity and electrophoretic and immunological properties identical to ER in MCF-7 breast cancer cells. HMG-1 interacts with ER and promotes ER-ERE binding in a concentration- and time-dependent manner. The effectiveness of HMG-1 to stimulate ER-ERE binding in the electrophoretic mobility shift assay depends on the sequence flanking the ERE consensus as well as the position of the latter in the oligonucleotide. We find that TAF(II)30 has no effect on ER-ERE binding either alone or in combination with ER and HMG-1. Although HMG-1 promotes ER-ERE binding, it fails to stimulate transcription initiation either in the presence or absence of hormone. In contrast, TAF(II)30, while not affecting ER-ERE binding, stimulates transcription initiation 20-fold in the presence of HMG-1. These results indicate that HMG-1 and TAF(II)30 act in sequence, the former acting to promote ER-ERE binding followed by the latter to stimulate transcription initiation.

BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function.

Breast cancer 1 (BRCA1)-associated breast cancers are mostly basal-like high-grade ductal carcinomas that frequently overexpress epidermal growth factor receptor (EGFR). Aberrant EGFR expression is correlated with disease progression, resistance to radiation and chemotherapy, and poor clinical prognosis. Although BRCA1 is involved in multiple cellular processes, its functional role in EGFR regulation remains enigmatic. Here, we report a previously unrecognized posttranscriptional mechanism by which BRCA1 regulates EGFR expression through the induction of miR-146a. We demonstrate that EGFR expression correlates negatively with BRCA1, whereas miR-146a levels increase with BRCA1. We show that BRCA1 binds to MIR146A promoter and activates transcription, which in turn attenuates EGFR expression. Knockdown of miR-146a in BRCA1-overexpressing cells negated this effect and suppressed its ability to inhibit proliferation and transformation. In archived triple-negative breast cancer samples, we show a strong positive correlation between BRCA1 and miR-146a expression. We also show that low expression of miR-146a strongly predicts positive lymph node status and is associated with distinctively poor overall survival of patients. Together, these observations provide an insight into a novel BRCA1miR-146aEGFR paradigm by which BRCA1 carries out an aspect of tumor suppressor function that is potentially amenable to therapeutic intervention.

The prephenate dehydrogenase component of the bifunctional T-protein in enteric bacteria can utilize L-arogenate.

The prephenate dehydrogenase component of the bifunctional T-protein (chorismate mutase:prephenate dehydrogenase) has been shown to utilize L-arogenate, a common precursor of phenylalanine and tyrosine in nature, as a substrate. Partially purified T-protein from Klebsiella pneumoniae and from Escherichia coli strains K 12, B, C and W was used to demonstrate the utilization of L-arogenate as an alternative substrate for prephenate in the presence of nicotinamide adenine dinucleotide as cofactor. The formation of L-tyrosine from L-arogenate by the T-protein dehydrogenase was confirmed by high-performance liquid chromatography. As expected of a common catalytic site, dehydrogenase activity with either prephenate or L-arogenate was highly sensitive to inhibition by L-tyrosine.

Papillary apocrine change of the breast: associations with atypical hyperplasia and risk of breast cancer.

Micropapillary patterns of apocrine change in human female breasts are common histological findings. They have been identified as cancer associated and implicated as an indicator of cancer risk in a predictive manner. This study has stratified papillary apocrine change (PAC) into categories of increasing complexity using a combination of cytological and histological pattern rules. Cases (2,876) were identified in a review of 10,357 benign breast biopsies. Of 5966 women, 1613 and PAC and were followed for a median of 20 years after biopsy for the development of invasive carcinoma of the breast. There was a slight association with cancer risk elevation, but most of this disappeared when women with concurrent, specifically identified patterns of atypical hyperplasia (AH) were excluded from the groups with PAC. The resultant relative risk was only 1.2 after women with AH were excluded. Only 1% of the reviewed biopsies demonstrated highly complex patterns of PAC, and 20% of these had coexistent lesions of AH. Women with highly complex patterns of PAC without AH did experience a relative risk of 2.4 (95% confidence interval = 0.77-7.04) but without statistical significance. More than one-half of all PAC patterns occurred without concurrent foci of lesions of proliferative disease that are associated with a slight elevation of breast cancer risk (at least 1.5 times); when present without proliferative disease, there was no suggestion of later breast cancer risk for PAC.

Construction and characterization of recombinant adenoviruses expressing human BRCA1 or murine Brca1 genes.

Recombinant adenoviruses expressing human BRCA1 (AdBRCA1), murine Brca1 (AdBrca1), three clinically relevant human mutant BRCA1 proteins (t340, C61G, and 1853Stop), or a murine Brca1 C-terminal deletion mutant were constructed and evaluated in vitro. These recombinants were capable of transducing high-level transgene expression to a wide variety of cell lines in vitro. Three independent methods were utilized to monitor cell growth following transduction with these recombinants. High-level expression of either the human or mouse wild-type BRCA1 protein was incompatible with maximal levels of cell growth. AdBRCA1 transduction inhibited the outgrowth of several human breast and ovarian cell lines in colony formation assays. Flow cytometric analysis revealed an accumulation of the transduced cells in the G0/G1 phase of the cell cycle. This BRCA1-mediated accumulation of cells in G0/G1 was accompanied by an increase in the cellular level of hypophosphorylated pRB. Ad mutant BRCA1 t340, C61G, and 1853Stop viruses were impaired, to varying degrees, in their ability to transduce a growth-arrested state to the target cells. Using these same three criteria, overexpression of murine Brca1 by AdBrca1 was also capable of transducing a growth-arrested state to human cells. Deletion of the C-terminus of Brca1 diminished this activity. This panel of adenoviruses may be useful reagents as part of an approach to understand the function of BRCA1/Brca1 in normal breast and ovary and help to define the tumor suppressor defect (s) conferred by clinical BRCA1 mutations in breast and ovarian cell tumorigenesis.

Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting.

The diagnosis of atypical ductal hyperplasia (ADH) at needle core breast biopsy (NCB) is typically regarded as an indication for surgical excision. Although ADH is an intermediate risk nonobligate precursor lesion, the rationale for further therapy is the result of a reported high prevalence of a concomitant more advanced lesion (typically ductal carcinoma in situ) as the index lesion. To assess whether certain histopathologic features of ADH in NCB are predictive of open biopsy outcomes, the authors correlated the extent and pattern of ADH in 47 core biopsies (11-or 14-gauge) with the subsequent surgical specimen. Extent of ADH on NCB was ascertained by determining the number of large ducts and/or terminal duct-lobular units affected, with involvement of one large duct or one terminal duct-lobular unit representing a single focus, involvement of one duct and one terminal duct-lobular unit as two foci, and so on. Of the 47 cases, ADH was restricted to < or =2 foci in 24 cases (51.1%), confined to 3 foci in 8 cases (17.0%), and involved > or =4 foci in 15 cases (31.9%). The corresponding histopathologic findings at excision were benign lesions without atypia (n = 14), focal residual ADH (n = 13), atypical lobular hyperplasia (n = 3), ductal carcinoma in situ (n = 15), and invasive mammary carcinoma (n = 2). When the number of foci of involvement by ADH on NCB (based on an average of 11.6 cores per case) was correlated with the open biopsy results, all cases of ADH limited to < or =2 foci had no worse lesion on excision, whereas ADH present in > or =4 foci was found to be a strong predictor of a more advanced lesion on excision (p <0.0001, chi2). When histologic pattern was evaluated, all cases of pure micropapillary ADH on NCB showed pure micropapillary ductal carcinoma in situ on excision.