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ABSTRACT: Previous studies have shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The extent, composition and biological significance of this field are only partially understood, but the molecular alterations in affected cells could provide mechanisms for limitless replicative capacity, genomic instability and a microenvironment that supports tumor initiation and progression. We demonstrate by microarray, qRT-PCR and immunohistochemistry a signature of differential gene expression that discriminates between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm and 5 cm from the margins of breast adenocarcinomas (TAHN-1 and TAHN-5, respectively). The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis and epithelial to mesenchymal transition (EMT). Myofibroblasts, which are mediators of wound healing and fibrosis, and intra-lobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of EMT, were both prevalent in TAHN-1 tissues, sparse in TAHN-5 tissues, and absent in normal tissues from reduction mammoplasty. Accordingly, EMT markers S100A4 and vimentin were elevated in both luminal and myoepithelial cells, and EMT markers α-smooth muscle actin and SNAIL were elevated in luminal epithelial cells of TAHN-1 tissues. These results identify cellular processes that are differentially activated between TAHN-1 and TAHN-5 breast tissues, implicate myofibroblasts as likely mediators of these processes, provide evidence that EMT is occurring in histologically normal tissues within the affected field and identify candidate biomarkers to investigate whether or how field cancerization contributes to the development of primary or recurrent breast tumors.
International Journal of Cancer 11/2010; 129(6):1310-21. · 5.44 Impact Factor
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Hugo Arias-Pulido,
Melanie Royce,
Yun Gong, Nancy Joste,
Lesley Lomo,
Sang-Joon Lee,
Nabila Chaher,
Claire Verschraegen,
Juanita Lara,
Eric R Prossnitz,
Massimo Cristofanilli
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ABSTRACT: GPR30 is a novel G protein-coupled estrogen receptor (ER) associated with metastases in breast cancer (BC) and poor survival in endometrial and ovarian tumors. The association of GPR30 expression with inflammatory breast cancer (IBC), an aggressive and commonly hormone-independent form of BC, has not been studied. GPR30, ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), and HER-2 expression were assessed by immunohistochemistry (and FISH for HER-2) in 88 primary IBCs. GPR30 expression was correlated with patient overall survival (OS), disease-free survival (DFS), pathologic variables, and other biomarkers. GPR30 expression was found in 69% of IBC cases. ER, PR, HER-2, and EGFR were found in 43, 35, 39, and 34% of IBC cases, respectively. GPR30 expression correlated inversely with ER expression (P = 0.02). Co-expression of ER and GPR30 was found in 24% of IBC samples; 19% expressed only ER and 46% expressed only GPR30. Univariate analysis showed no association between GPR30 expression and OS or DFS. However, co-expression of ER and GPR30 was associated with improved OS (P < 0.03) and marginally with DFS (P < 0.06); the absence of both ER and GPR30 was associated with worse OS and DFS (P = 0.03 for both). Multivariate analysis identified ER as an independent prognostic factor of OS (P = 0.008) and DFS (P = 0.02). The majority of IBC tumors are GPR30-positive, suggesting that estrogen signaling may be active in ER-negative IBC patients. These findings suggest potential new therapeutic targets for IBC such as novel endocrine agents or direct modulation of GPR30.
Breast Cancer Research and Treatment 11/2009; 123(1):51-8. · 4.43 Impact Factor
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Nancy Joste
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ABSTRACT: Screening for cervical cancer by the Papanicolaou or Pap test is a complex and multistep process. From the clinician's examination room to the cytology laboratory, the Pap test involves numerous laboratory personnel, different test types, and the possibility of computer-assisted screening and ancillary testing. The laboratory has in place well-defined procedures to ensure both error reduction and specimen quality to produce reliable Pap test results. The Bethesda System 2001 provides guidance and criteria for both specimen adequacy and diagnostic criteria. Understanding laboratory procedures in Pap testing aids in clinical understanding of tests and results and contributes to effective communication between the pathologist and those involved in patient management of women with cervical abnormalities.
Obstetrics and Gynecology Clinics of North America 01/2009; 35(4):549-63; viii. · 1.70 Impact Factor
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ABSTRACT: To assess telomere DNA content (TC) and the number of sites of allelic imbalance (AI) as a function of breast cancer progression.
TC and AI were determined in 54 histologically normal tissues, 10 atypical ductal hyperplasias (ADH), 122 in situ ductal carcinomas (DCIS) and 535 invasive carcinomas (Stage I-IIIA).
TC was altered in ADH lesions (20%), DCIS specimens (53%) and invasive carcinomas (51%). The mean number of sites of AI was 0.26 in histologically normal group tissue, increased to 1.00 in ADH, 2.94 in DCIS, and 3.07 in invasive carcinomas. All groups were statistically different from the histologically normal group (P < 0.001 for each); however, there was no difference between DCIS and the invasive groups.
Genomic instability increases in ADH and plateaus in DCIS without further increase in the invasive carcinomas, supporting the notion that invasive carcinomas evolve from or in parallel with DCIS.
Breast Cancer Research and Treatment 10/2008; 117(1):17-24. · 4.43 Impact Factor
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American journal of clinical oncology 11/2007; 30(5):564-5. · 2.21 Impact Factor
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ABSTRACT: High-risk human papillomaviruses (HPVs), specifically HPV-16 and -18, have been associated with the development of carcinoma in situ (CIS) and of invasive cervical cancer (CC). However, only a small fraction of HPV-infected women will show signs of disease progression, suggesting that other factors in the carcinogenic pathway are needed. We previously demonstrated that human leukocyte antigen (HLA) DRB1*1501-DQB1*0602 (high risk) was associated with the development of CIS and CC tumors in HPV-16-positive patients. To characterize the molecular changes that could be relevant to tumor progression, we compared the extent of loss of heterozygosity (LOH) on chromosome 6 in HPV-16-positive CIS patients who were carriers of high-risk and neutral HLA haplotypes. CIS and CC cases demonstrated similar LOH patterns. A wide range of LOH frequencies was found at 6p (10-53%) and 6q (5-28%) in CIS cases, suggesting that LOH is an early event in the carcinogenic process. A comparative analysis of LOH frequencies in the high-risk versus the neutral HLA haplotypes showed a statistically significant difference in the extent of LOH at 6p24-p25 (58.6% versus 25.8%; P = 0.018) and at 6p21.3 (79.3% versus 35.5%; P = 0.001), a region that contains the HLA complex. LOH at this region could affect genes encoding HLA class I-II molecules, as well as factors responsible for the assembly, transport, and stable expression of HLA molecules. These losses may be a reflection of both an abnormal immune response and a general genome-wide instability resulting from virus persistence.
Genes Chromosomes and Cancer 09/2004; 40(4):277-84. · 3.31 Impact Factor
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ABSTRACT: Synovial sarcomas (SS) are characterized by the t(X;18)(p11;q11) translocation and its resultant fusion gene, SYT-SSX. Two homologues of the SSX gene (ie, SSX1 and SSX2) are involved in the vast majority of SS and the SYT-SSX1 type of fusion has been associated with inferior clinical outcome. Thus, detection of the presence and type of SYT-SSX fusion is critical for diagnosis and prognosis in SS. Identification of SYT-SSX fusion type is typically accomplished by reverse-transcription polymerase chain reaction (RT-PCR) followed by a post-PCR analytic method. As mRNA nucleotide sequences of the SSX1 and SSX2 segments involved in the SYT-SSX fusion are nearly identical, post-PCR methods must be highly discriminatory. We describe a novel method to identify and differentiate these two chimeric transcripts using RT-PCR followed by fluorescent thermostable ligase detection reaction (f-LDR), microparticle bead capture and flow cytometric detection. Evaluation of this unique approach in 11 cases of SS without prior knowledge of SYT-SSX status, six cases of control sarcomas (CS) and three hematopoietic cell lines, revealed that the f-LDR technique was rapid, unambiguous, and highly specific. The f-LDR results were compared to XmnI enzyme digestion patterns and sequencing of PCR products, revealing a 100% concordance for all cases of SS with regards to SYT-SSX transcript type. In addition, there was a strong association of transcript type detected by f-LDR and morphological subclassification of SS, as previously reported. We conclude that this f-LDR method with flow-based detection is a robust approach to post-PCR detection of specific nucleotide sequences in SS and may be more broadly applicable in molecular oncology.
Journal of Molecular Diagnostics 06/2003; 5(2):127-35. · 3.58 Impact Factor
