Faculty Bibliography
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227
Pregnancy-induced chromatin remodeling in the breast of postmenopausal women
Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP breast, nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast, there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing and noncoding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full-term pregnancy.
PMCID:3350833
PMID: 22025034
ISSN: 0020-7136
CID: 162482
Atypical ezrin localization as a marker of locally advanced breast cancer
Locally advanced breast cancer (LABC) was initially characterized as a large primary tumor (>/=5 cm), associated with or without skin or chest-wall involvement, fixed axillary lymph nodes, or disease spread to the ipsilateral internal mammary or supraclavicular nodes. Since 2002, LABC has been reclassified to include smaller stage IIB tumors (2 to <5 cm) with lymph node involvement, or stages IIIA-IIIB (>/=5 cm) with or without nodal involvement. Despite the rather common presentation of LABC, it remains a poorly understood and highly variable clinical presentation of breast cancer that is a challenge to treatment. Here, we characterized a panel of breast tumors of known stage, grade, and key clinical-pathological parameters for the expression of the protein ezrin, which is involved in promoting signaling of the PI3K-Akt-mTOR pathway in response to extracellular and tumor micro-environmental signals, and is involved in breast cancer invasion and metastasis. We show that ezrin, which resides primarily in the apical membrane in normal breast epithelium, relocalizes primarily to the cytoplasm in >80 % of traditional (T3) invasive ductal LABC tumors (>/=5 cm). Cytoplasmic ezrin is very strongly associated with a single characteristic in breast cancer-large tumor size. In contrast, in large non-malignant fibroadenomas, ezrin staining was similar to that of normal breast epithelium. Small (T1, 1 cm) invasive ductal carcinomas displayed largely apical membrane and perinuclear ezrin localization with weak cytoplasmic staining. Cytoplasmic ezrin localization was also associated with positive lymph node status, but no other clinical-pathological features, including hormone receptor status, histological or nuclear grade of tumor cell. The cytoplasmic relocalization of ezrin may therefore represent a novel marker for large malignant tumor size, reflecting the unique biology of LABC.
PMID: 22415480
ISSN: 0167-6806
CID: 162566
Pathway Analysis of Genome-wide Association Study Data Highlights Pancreatic Development Genes as Susceptibility Factors for Pancreatic Cancer
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease associated SNPs whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3,851 pancreatic cancer cases and 3,934 control participants pooled from 12 cohort studies and 8 case control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response, and apoptosis (P = 2.0 x 10(-6), 1.6 x 10(-5), 0.0019, 0.019, and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO, and SHH), the pancreatic development pathway remained significant (P = 8.3 x 10(-5)), while the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G, and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response; and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
PMCID:3405651
PMID: 22523087
ISSN: 0143-3334
CID: 165599
The diagnosis, treatment, and follow-up of cesarean scar pregnancy
OBJECTIVE: The diagnosis and treatment of cesarean scar pregnancy (CSP) is challenging. The objective of this study was to evaluate the diagnostic method, treatments, and long-term follow-up of CSP. STUDY DESIGN: This is a retrospective case series of 26 patients between 6-14 postmenstrual weeks suspected to have CSP who were referred for diagnosis and treatment. The diagnosis was confirmed with transvaginal ultrasound. In 19 of the 26 patients the gestational sac was injected with 50 mg of methotrexate: 25 mg into the area of the embryo/fetus and 25 mg into the placental area; and an additional 25 mg was administered intramuscularly. Serial serum human chorionic gonadotropin determinations were obtained. Gestational sac volumes and vascularization were assessed by 3-dimensional ultrasound and used to monitor resolution of the injected site and outcome. RESULTS: The 19 treated pregnancies were followed for 24-177 days. No complications were observed. After the treatment, typically, there was an initial increase in the human chorionic gonadotropin serum concentrations as well as in the volume of the gestational sac and their vascularization. After a variable time period mentioned elsewhere the values decreased, as expected. CONCLUSION: Combined intramuscular and intragestational methotrexate injection treatment was successful in treating these CSP.
PMID: 22607667
ISSN: 0002-9378
CID: 170423
Detectable clonal mosaicism and its relationship to aging and cancer
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
PMCID:3372921
PMID: 22561519
ISSN: 1061-4036
CID: 169562
Premenopausal serum androgens and breast cancer risk: A nested case-control study
ABSTRACT: INTRODUCTION: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited. METHODS: A case-control study nested within the NYU Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated. RESULTS: Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI) , 0.9-2.3), 1.2 (95% CI, 0.7-1.9), 1.4 (95% CI, 0.9-2.3) and 1.8 (95% CI, 1.1-2.9; Ptrend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7-1.8), 1.5 (95% CI, 0.9- 2.3), 1.5 (95% CI, 0.9-2.3), 1.8 (95% CI, 1.1-2.8, Ptrend = 0.01). A marginally significant positive association was observed with androstenedione (p = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls). CONCLUSIONS: Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (i.e. a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone to breast cancer risk prediction models for women between the ages of 40 and 50 should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.
PMCID:3496150
PMID: 22339988
ISSN: 1465-5411
CID: 157302
Global breast cancer: the lessons to bring home
Breast cancer is the most common cancer affecting women globally. This paper discusses the current progress in breast cancer in Western countries and focuses on important differences of this disease in low- and middle-income countries (LMCs). It introduces several arguments for applying caution before globalizing some of the US-adopted practices in the screening and management of the disease. Finally, it suggests that studies of breast cancer in LMCs might offer important insights for a more effective management of the problem both in developing as well as developed countries.
PMCID:3262607
PMID: 22295243
ISSN: 2090-3189
CID: 169459
Factors associated with inflammation markers, a cross-sectional analysis
Epidemiological studies have reported associations between circulating inflammation markers and risk of chronic diseases. It is of interest to examine whether risk factors for these diseases are associated with inflammation. We conducted a cross-sectional analysis to evaluate whether reproductive and lifestyle factors and circulating vitamin D were associated with inflammation markers, including C-reactive protein, cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFalpha), and cytokine modulators (IL-1RA, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1/R2), among 616 healthy women. We confirmed associations of several inflammation markers with age and BMI. We also observed significantly higher levels of certain inflammation markers in postmenopausal vs. premenopausal women (TNFalpha, sIL-1RII, sIL-2Ra), with increasing parity (IL-12p40), and with higher circulating 25(OH) vitamin D (IL-13) and lower levels among current users of non-steroidal anti-inflammatory drugs (NSAIDs) (IL-1beta, IL-2, IL-10, IL-12p70, and IL-12p40), current smokers (IL-4, IL-13, IL-12p40), and women with a family history of breast or ovarian cancer (IL-4, IL-10, IL-13). Our findings suggest that risk factors for chronic diseases (age, BMI, menopausal status, parity, NSAID use, family history of breast and ovarian cancer, and smoking) are associated with inflammation markers in healthy women
PMCID:3245985
PMID: 22015105
ISSN: 1096-0023
CID: 141702
Re: Long-term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS
PMID: 21969339
ISSN: 1460-2105
CID: 141699
Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome
OBJECTIVE: The objective of the study was to investigate whether resistance to annexin A5 anticoagulant activity (AnxA5) occurs in women with histories for obstetric complications of antiphospholipid syndrome (Obs-APS) and whether this correlates with antibody recognition of domain 1 of beta2-glycoprotein. STUDY DESIGN: One hundred thirty-six women with antiphospholipid antibodies, including 70 with histories for Obs-APS and 30 controls, were investigated. RESULTS: Women with Obs-APS showed resistance to AnxA5 activity (median, 216%; range, 130-282% vs controls; median, 247%; range, 217-283%; P < .0001) and elevated levels of anti-domain I immunoglobulin (Ig) G (optical density: median, 0.056; range, 0.021-0.489 vs median, 0.042; range, 0.020-0.323; P = .002). Those in the lowest tertile of AnxA5 anticoagulant ratios had an odds ratio for Obs-APS of 58.0 (95% confidence interval, 3.3-1021.5). There was an inverse correlation between levels of annexin A5 anticoagulant activity and anti-domain I IgG. CONCLUSION: Resistance to AnxA5 anticoagulant activity is associated with antibody recognition of domain I of beta2-glycoprotein I and identifies a subset of women with histories for Obs-APS
PMCID:3205287
PMID: 21784397
ISSN: 1097-6868
CID: 150007
