bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Claudin- 5 and the Paracellular Barrier Function in Endothelial Cells during Invasion of Breast Cancer Cells.
Authors: Escudero-Esparza A. , Martin T. , Jiang W. 
Published: December 2010

Abstract
Material and Methods: Human endothelial (HECV) and breast cancer cells (MDA-MB-231) were used to assess the effect of over-expression (HECVCL-5, MDACL-5) or knockdown (HECVDCL-5, MDADCL-5) of Claudin-5. Cell adhesion and growth were evaluated using in vitro assays. An in vivo tumour model using athymic nude mice was used to assess growth of tumours. Transendothelial and transepithelial resistance (TER) was employed to measure changes in TJ function. Cellular motility was analyzed using Cytodex-2 bead motility assay. ECIS (electrical cell impedance sensing) was used to assess the attachment and migration of the cells.Results: There were no significant differences in in vitro growth of cells that over-expressed or had knockdown of Claudin-5 (both HECV and MDA-MB-231 cells). Expression of CL5 in both HECV and MDA-MB-231 did not have a significant impact on in vivo growth. There were however, significant differences in adhesion between control cells (HEVCpEF6) and HECVCL-5, HECVDCL-5 (changes in adhesion: HEVC pEF6 vs. HECVCL-, P&gt;0.05; HECVDCL-5, P=0.046). There was a distinct modulation of TJ function as assessed using TER. HECVDCL-5 cells exhibited increased resistance compared to HEVC pEF6 and HECVCL-5 (change in TER: HEVC pEF6: -151.33±6.11 vs. HECVCL-5 -187±1.73, HECVDCL-5-89.33±2.08, P &lt;0.01). There was no difference in TER in MDA CL-5 and MDADCL-5cells. HGF, a powerful motogen and modulator of TJ function, caused a significant increase in TER in HECVCL-5 and HECVDCL-5, but resulted in a significant decrease in TER in MDA-MB-231 cells. Motility studies revealed that HECVCL-5 and MDA CL-5 after treatment with HGF cells were significantly more motile than cells without treatment (HECVCL-5 vs. HECVCL-5+HGF, P=0.015; MDACL-5 vs. MDACL-5+HGF, P=0.033). There was no difference in motility in HECVDCL-5 cells, however, MDADCL-5 cells were significantly less motile after treatment with HGF (P=0.017). Interestingly, ECIS results showed that the ROCK inhibitor Y27632 inhibited the attachment and migration of HECVCL-5 cells but was no longer able to inhibit attachment and migration of HECVDCL-5 cells.Discussion: These results demonstrate for the first time that Claudin-5 can be modulated to effect changes in cell motility, attachment and TJ function in human endothelial and breast cancer cells. Moreover, there appears to be a link between Claudin-5 expression and cell motility, particularly with respect to the ROCK signalling cascade.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6170.
Mammary Tumors in STAT1-Deficient Mice Recapitulate Characteristics of Human Luminal Breast Cancers.
Authors: Chan S. , Schreiber R. 
Published: December 2010

Abstract
Human breast cancer of the luminal subtype represents approximately 70% of all newly diagnosed breast cancers. This particular subtype of tumors are estrogen receptor α (ERα)-positive and/or progesterone receptor (PR)-positive. However, 50% of these patients do not derive benefit from endocrine therapy. One obstacle in the study of hormone receptor-positive breast cancer is that there is currently a deficit in murine models that can fully recapitulate the biology of this highly prevalent breast cancer subtype. Here we show that mice lacking the transcription factor signal transducers and activators of transcription 1 (STAT1) spontaneously developed mammary gland adenocarcinomas that showed remarkable similarities to human luminal breast cancer at histopathological, biological and molecular levels. More than 90% of the tumor cells in both early and advanced lesions were ERα+ and/or PR+. STAT1-/- mammary tumor cells failed to grow in ovariectomized mice, demonstrating that these tumors are addicted to ovarian hormones for proliferation. Supplementing with exogenous estrogen was sufficient to rescue tumor growth in ovariectomized mice. STAT1 functions, at least in part, as an intrinsic tumor suppressor since reconstitution of STAT1 expression in STAT1-/- mammary tumor cells induced spontaneous apoptosis. Induction of cell death required the critical tyrosine residue at position 701, suggesting that the transcriptional function of STAT1 is involved in tumor suppression.In contrast to the anti-oncogenic effect of STAT1, STAT3 was constitutively phosphorylated by JAK2 in the STAT1-/- mammary tumor cells. Inhibition of JAK2 or STAT3 activation resulted in tumor cell death, indicating that STAT3 promotes tumor cell survival. Gene expression profiles of the STAT1-/- mammary tumors showed significant overlaps with that of the human luminal breast cancers, strongly supporting that the STAT1-/- mammary tumors recapitulate the molecular signatures of human luminal breast cancers. Consistent with the results that STAT1 can act as an intrinsic tumor suppressor, approximately 10% of the human ERα+ breast cancer cases exhibit either undetectable or very low level of STAT1 in the mammary epithelial compartment. This study uncovers a unique role of STAT1 in suppressing mammary gland tumorigenesis. Importantly, this physiologically relevant model of human luminal breast cancer will provide an exceptional tool for the development and evaluation of novel therapeutics.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 65.
Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy.
Authors: Tekmal R. , Nair H. , Huffman S. , Kirma N. , Rao P. , Evans D. , Ramana K. , Srivastava S. 
Published: December 2010

Abstract
Breast cancer is the most commonly diagnosed form of cancer in women. Among breast cancer patients about 2/3 are initially hormone sensitive or estrogen receptor (ER) positive and respond to endocrine therapy. Aromatase inhibitors (AI's) are superior class of hormonal therapeutic agents effectively control ER positive breast cancer in postmenopausal women. Acquired resistance to AI's is expected to be an emerging serious problem in clinics and recent studies have shown that tumors use adaptive signaling mechanisms to overcome AI sensitivity. Thus there is an urgent need for newer treatment modalities. Combination of endocrine and non endocrine agents that block these signaling pathways may prevent or delay the adaptive mechanism and thereby onset of resistance to hormonal therapy. In our study we have found that Fidarestat, an aldose reductase (enzyme which catalyzes the rate limiting step of glucose to fructose or sorbitol formation in polyol pathway) inhibitor effectively re-sensitize letrozole resistant LTLT-Ca breast cancer cells to letrozole. 1µM of fidarestat + 1uM letrozole was found very effective in inducing maximum cell death in LTLT-Ca cells when compared to fidarestat alone. The combination treatment not only restored ER-α levels but also down regulated HER2/MAPK signaling proteins. Aldose reductase siRNA (100nM)- treated MCF-7/Aro and MCF-7 cells upregulated ER-α in western blot and ER-functionality assays. On the other hand in aldose reductase-siRNA- treated LTLT-Ca cells, ER-α levels were down- regulated as in fidarestat treatment. Pretreatment of LTLT-Ca with fidarestat for one week showed reduced proliferation of cells and the effect was maintained until four passages with 1µM letrozole alone. Fidarestat treatment up-regulated E2-mediated transcription in LTLT-Ca cells. In order to enhance the efficacy and targeted delivery of fidarestat in LTLT–Ca cells we have used a nanoparticle-based therapeutic formulation. Folate receptor, highly expressed on epithelial carcinomas, could be a potential molecular target for tumor selective drug delivery. Physcio-chemically well characterized Fidarestat–folate nanoparticles (FFNP's) were prepared to increase the tumor selective intracellular delivery. FFNP's were found superior in exerting cytotoxicity when compared to fidarestat alone. Combination therapy was equally effective in controlling LTLT-Ca cell growth using xenograft model. Taken together, the increased glucose metabolism in LTLT-Ca cells may be critically contributing to chemotherapeutic resistance by increasing drug metabolism and decreasing uptake. Hence targeting aldose reductase in endocrine resistance may be attractive alternative to increase the sensitivity of hormonal therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 67.
Central Review of ER, PgR and HER2 in BIG 1-98 Evaluating Letrozole vs. Letrozole Followed by Tamoxifen vs. Tamoxifen Followed by Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women with Hormone Receptor-Positive Breast Cancer.
Authors: Viale G. , Regan M. , Dell'Orto P. , Mastropasqua M. , Rasmussen B. , MacGrogan G. , Braye S. , Orosz Z. , Giobbie-Hurder A. , Neven P. , Knox F. , Oehlschlegel C. , Thuerlimann B. , Coates A. , Goldhirsch A. 
Published: December 2010

Abstract
Background: The BIG 1-98 trial, a large international Phase III study, evaluated letrozole (Let) for 5 years (n=1546) vs. Let for 2 years followed by tamoxifen (Tam) for 3 years (L→T; n=1540) and vs. Tam for 2 years followed by Let for 3 years (T→L; n=1548) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. Patients with HER2-positive disease did not receive trastuzumab. Efficacy results were presented in SABCS 2008 and showed that neither of the sequential therapy arms significantly improved disease-free survival (DFS) compared with letrozole alone. Centrally-assessed ER, PgR and HER2 have now been evaluated as potential predictive factors for treatment selection.Methods: Tumor blocks for 3975 of the 4634 (86%) patients on these three treatment arms were centrally collected and assessed by the IBCSG Central Pathology Laboratory. The tumors were evaluated for ER and PgR content by immunohistochemistry (IHC), and for HER2 immunoreactivity by IHC and by FISH for IHC 1+ or 2+ tumors. DFS according to centrally-assessed ER, PgR and HER2 status was analyzed using multivariable Cox modeling. STEPP methodology was used to explore patterns of DFS differences according to quantitative values of receptor levels (% staining cells).Results: Upon central review, 3885 tumors were confirmed to express ER and are the focus of this analysis. PgR expression did not predict differential treatment effects among the 3 treatment arms. With only 240 (6.2%) HER2-positive tumors, there was a suggestion of differential treatment benefit relative to HER2 status, in particular of a benefit of Let for 5 yrs over Tam→Let in HER2-positive tumors.Discussion: Given the caveat of a low prevalence of HER2-positive tumors and absence of HER2-directed therapy in the BIG 1-98 trial population, there is a suggestion that Let for 5 years may be a better option than a sequence of Tam and Let among women with HER2-positive tumors. Thus it may be better to initiate and continue treatment of endocrine-responsive, HER2+ tumors with Let rather than a sequence of Tam and Let.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 76.
Joint Disorders Frequency and Structural Changes during Anastrozole Adjuvant Treatment in Early Breast Cancer: A Prospective Trial (D5392L00013).
Authors: Delozier T. , Daban A. , Dieras V. , Mauriac L. , Gligorov J. , Tubiana-Hulin M. , Goldwasser F. , Briot K. , Roux C. , Amrate A. , Guastalla J. 
Published: December 2010

Abstract
Background:Aromatase inhibitors (AIs) are standard adjuvant endocrine-therapy in postmenopausal women with hormone-sensitive breast cancer. However, main side effects reported are musculoskeletal symptoms. The pathogenic and anatomic features of AI-induced arthralgia have not been clearly defined. The objective of the study was to describe the joint symptoms and structural joint changes in women received adjuvant anastrozoleMethods: Postmenopausal women with hormone receptor positive early breast cancer were enrolled in this open, multicentre trial. Anastrozole was administrated 1mg/day p.o. All of them were naïve of AI and tamoxifen treatment. Patients were followed one year with clinical examination every 3 months, ultrasound (US) examination every 6 months, measurements of inflammation biomarkers and cartilage biomarkers of degradation U-CTX-II (urinary C-terminal crosslinked telopeptide of type II collagen) every 6 months and X-rays at baseline and 12 monthsResults: From June 2006 to December 2007, one hundred and fourteen patients (114) were included and 106, with a median age of 61.5 (49-79) years, were followed-up for 1 year.Overall, 33% of patients were previously treated by chemotherapy, (anthracyclines 97%, taxanes 63 %) and 40.6% were receiving hormone replacement therapy (HRT) at tumour diagnosis. The prevalences of arthralgia were 40.6, 59.1 and 60.6 % at baseline, 6 months and 12 months respectively.Among the 63 (59.4%) patients without arthralgia at baseline, 37 patients presented with arthralgia during treatment (26 between baseline and M6, 11 between M6 and M12) with median time to onset of 4 months.In univariate logistic analysis, significant determinant factors of joint disorders at 12 months were previous osteoarthritis and personal history of arthralgia but not the previous HRT or previous adjuvant chemotherapy with taxanes. In multivariate analysis, none of those factors were significant.Clinical examination by rheumatologist and US examination did not show any significant changes of the number of synovitis and tenosynovitis over 12 months.There were no significant changes of the U-CTX-II levels and of joint damages assessed by radiographs. Inflammation biomarkers did not significantly change over 12 months.Conclusion: This prospective study with a systematic rheumatologist follow up of the patients showed that arthralgia occurs early after the beginning of anastrozole therapy (first 6 months); and suggest that joint disorders were not associated with any cartilage degradation after 1 year of treatment.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 801.
Protective Effect of Estrogen (E2) and Increased Risk of E2 Plus Progestin (Prog) on Breast Cancer (BrCa). The 2009 Review of the Women's Health Initiative (WHI) Hormone Replacement Therapy (HRT) Published Trials.
Authors: Ragaz J. , Le N. , Budlovsky J. , Spinelli J. 
Published: December 2010

Abstract
INTRODUCTION & METHODOLOGY.The objective of this review is to identify from the two WHI published randomized HRT trials the BrCa risk or benefit, with a special focus on different impact of E2-alone vs E2+Prog on human breast carcinogenesis (BrCa-genesis).In the 1st trial (JAMA 2002, 2007), healthy women age 50 - 79 were randomized to E2 plus Prog versus placebo (Plac). Reviewed were Hazard ratios (HRs) for all pts and also for those with or without prior Hormone use. Mean follow up was 5.2 years.In the 2nd trial (JAMA 2004, 2006), women with hysterectomy age 50 - 79 were randomized to E2 alone (without Prog) versus Plac. Mean follow up was 7.1 years. Reviewed were all pts, and also subsets with or without prior E2 or Prog; with or without prior history of Benign Breast Disease (PHBrD); and with or without prior history of a 1st degree relative with BrCa (PH1stRelBrCa).RESULTS.Invasive BrCa incidence:N (%)HR95% C.I.1st TrialAll participants:16,608 (100%)1.260.83 - 1.97No prior Hormone use:12,304 (74.1%)1.060.81 - 1.38Prior Hormone use &lt;5 yrs:3,005 (18.1%)2.131.15 - 3.94*Prior Hormone use 5 - 10 yrs:783 (4.7%)4.611.01 - 21.02*2nd TrialAll participants:10,739 (100%)0.800.62 - 1.04No prior hormone use:5,763 (53.7%)0.650.46 - 0.92*Prior E2 use:4,976 (46.3%)0.980.67 - 1.44Prior E2 + PROG use:468 (4.4%)2.350.60 - 9.14No PHBrD:7,681 (71.5%)0.570.41 - 0.78*No PH1stRelBrCa8,554 (80.0%)0.680.50 - 0.92*CONCLUSION:1. Results from the 1st trial show that concomitant use of E2 with Prog, particularly in women with prior Hormone use, is associated with increased BrCa hazards.2. The results of the 2nd HRT trial indicate that use of HRT with E2 alone is associated with a reduction in BrCa incidence, significant in the majority of women with no prior BrCa risk factors. Also the results show that prior Prog but not prior E2 elevate the risk.3. These data indicate that HRT with E2 alone has a BrCa protective effect, while adding Prog increases the risk.4. These results are also compatible with a dual E2 effect on BrCa-genesis, where exogenous E2 are protective, but endogenous E2 [endE2] are carcinogenic, as shown from decades of anti-end E2 research with Tamoxifen, oophorectomy or Aromatase inhibitors.5. Based on these data we propose that in women with hysterectomy and no prior history of risk factors, the use of HRT with E2 alone as chemoprevention is plausible, and needs urgent verification.* significance, "p" &lt;0.05.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 908.
p16 Expression and Breast Cancer Risk in Women with Atypical Hyperplasia.
Authors: Santisteban M. , Berman H. , Reynolds C. , Gauthier M. , Frost M. , Vierkant R. , Pankratz S. , Anderson S. , Tlsty T. , Hartmann L. 
Published: December 2010

Abstract
Background: p16 is a nuclear protein encoded by the p16INK4a gene that regulates the G1-S cell cycle checkpoint. Its overexpression could reflect normal proliferative arrest, but also the evolution of carcinogenic processes that have overcome the p16 block, with progression from hyperplasic lesions to invasive breast cancer. Our aim with this study was to correlate p16 expression, both individually and in combination with expression of COX-2 and Ki67, with subsequent risk of breast cancer among women with atypical hyperplasia. Methods: p16 expression was assessed by immunohistochemical assays in archival paraffin-embedded, formalin-fixed sections from 233 women with atypia whose biopsy specimens were obtained via surgical excision at the Mayo Clinic from January 1, 1967, through December 31, 1991. p16 expression was scored as percent of cells positive and intensity of staining. Risk factor information and follow-up for breast cancer events were obtained via study questionnaire and the medical records. Standardized incidence ratios (SIRs) were used to compare observed numbers of breast cancer events to population-based expected counts, both at 10 years and over the entire course of follow-up. Results: Forty-seven patients (20%) developed breast cancer with a mean follow-up of 14.3 (SD=6.96) years. The overall risk of developing breast cancer was not modified by increasing p16 overexpression (low percent of staining with RR=3.89, 95% CI=2.72 to 5.56; high percent of staining with RR=3.91, 95% CI=2.43 to 6.28; similar results for intensity of staining). However, overexpression of both p16 and COX2 conveyed a stronger risk of breast cancer (SIR=4.01, 95% CI 2.28 to 7.07) as compared to dual low expression (SIR 1.78, 95% CI 0.67-4.74). Moreover, overexpression of both Ki67 and p16 was related to a higher 10-year breast cancer risk (SIR 6.25, 95% CI 2.35-16.6) as compared to low expression of both markers (SIR 0.87, 95% CI 0.22-3.49). Conclusions: although single expression of p16 does not stratify breast cancer risk, its overexpression in concert with biomarkers that reflect other carcinogenic processes (e.g. Ki67 and COX2) could help to define risk of tumor development.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 910.
Results of Breast Conservation Therapy of DCIS without Radiation: Comparison to Mastectomy in a Prospective Study.
Authors: Decker T. , Kettritz U. , Obenaus R. , Morack G. , Jacob R. 
Published: December 2010

Abstract
Aim:To assess the long-term outcome for women with DCIS of the breast treated in clinical practice by breast conservation surgery (BCS) without definitive breast irradiation in comparison to those treated by mastectomy (ME).Patients and MethodsWe studied 534 (of 599) patients with DCIS treated between 1992 and 2003 in a German regional cancer center. 287 patients underwent BCS without adjuvant radiotherapy whereas 247 patients were treated by ME. The decision was made after radiologic-pathological correlation and based on results of standardized pathology work-up including radiograms of whole specimen and slices. The decision was based on margins in 6 directions and maximum size of DCIS. In all cases with margins &lt;10 mm a re-resection was performed, all patients with lesions &gt;40 mm with margins &lt;10 mm were advised to ME. All patients who decided for ME although their lesions did not show these criteria as all patients who could not followed were excluded. The median follow-up for the study population was 82 months.ResultsDuring the follow-up period 8/287 (2.8 %) patients of the BCS group and 10/247 (4.0 %) patients of the ME showed local recurrences. 2/8 (25 %) and 5/10 (50 %) of the recurrences were invasive. Neither regional nor systemic metastases were found, no patient died. Regarding these events there was no statistical significant difference between both groups.The BCS and ME group differed significantly in maximum diameters of DCIS (median 23 mm vs. 64 mm; p&lt;0.001). There was no significant difference in nuclear grade distribution (BCS: 52 (18 %) grade 1, 115 (40 %) grade 2, 120 (42 %) grade 3; ME: 54 (22 %) grade 1, 99 (40 %) grade 2, 94 (38 %) grade 3).ConclusionsOur results support that under the precondition of margins &gt;10mm, patients treated with BCS without radiotherapy can expect very low local recurrence risks similar to those treated with ME. This study continues to support the incremental benefit of margin width on recurrence under the precondition of standardised readilogic and pathological work-up of the specimens.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 953.