bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4590: Characterization of an epithelial micro-pattern within ducts and lobules of the human breast: The topography of estrogen receptor expression
Authors: Villadsen Rene , Fridriksdottir Agla Jael , Kim Jiyoung , Rønnov-Jessen Lone , Petersen Ole W. 
Published: February 2011

Abstract
Estrogen receptors (ERs) function as relays between oscillating levels of circulating estrogen and micro-environmental cues for growth and differentiation during breast development, function and carcinogenesis, yet the cells that express ERs are poorly understood. Using an antibody library and multicolour imaging, we have found that ERs, which are expressed in an apparently unpredictable manner throughout ducts and lobules of the human breast, are in fact patterned by an underlying compartment of cells with a unique differentiation program and topography. Furthermore, we show that while ER-occupancy of this compartment is highly variable from zero to full between individual ducts and lobules, its average size is relatively constant. Moreover, vacancy is associated with a slightly higher proliferative activity as revealed by staining for Ki-67 and the ER-compartment cells are able to form acinus-like colonies inside a reconstituted basement membrane. In human breast cancers staining for the ER-compartment program revealed that fifty percent of a sample of apparently ER-negative tumors in reality was composed of ER-compartment cells. These results establish an anatomical foundation for the expression of ER in the human breast and a link between a broader sense, normal ER-compartment and a subset of ER-negative albeit luminal human breast carcinomas.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4590.
Abstract 4600: The role of COUP transcription factors in Tamoxifen resistant breast cancer cells
Authors: Maniya Omar Z. , Zwart Alan , Chen Li , Xuan Jianhua , Clarke Robert , Riggins Rebecca B. 
Published: February 2011

Abstract
Breast cancer affects 180,000 women in the United States every year, killing over 40,000 of them. The most common type of breast cancer, which expresses the Estrogen Receptor (ER+), has been clinically treated with the antiestrogen Tamoxifen (TAM) for decades. However, up to 35% of patients taking TAM may develop resistance to the drug. This may be related to the fact that ER+ breast cancers are divided into Invasive Lobular Carcinomas (ILC) and Invasive Ductal Carcinomas (IDC), which may have different mechanisms for TAM resistance. Thus, TAM resistance represents a formidable challenge in the treatment of breast cancer.
TAM is an antagonist of estrogen receptor alpha (ERalpha), and prevents estrogen-dependent growth signaling in breast tissues. We have published that overexpression of the orphan nuclear receptor, estrogen related receptor gamma (ERRgamma), leads to TAM resistance in ER+ breast cancer cell lines derived from ILC. We have recently found that ERRgamma is also overexpressed in the IDC-derived RR TAM resistant cell line (but not in other models of TAM resistance). This leads us to hypothesize that other orphan nuclear receptors may have been overlooked in prior studies of TAM resistance, and that different members of the nuclear receptor superfamily play unique roles in ILC- and IDC-derived TAM resistant breast cancer.
To test this hypothesis, we profiled mRNA expression of the nuclear receptor superfamily in two pairs of TAM sensitive and resistant cells: the IDC-derived MCF7 and RR, and the ILC-derived MDA-MB-134VI and TAM-R. Expression of two members of the COUP transcription factor family was significantly changed. NR2F1 (COUP-TFI) was highly overexpressed in RR cells, and NR2F2 (COUP-TFII) was highly overexpressed in both RR and TAM-R cells relative to sensitive controls. These findings are highly significant as COUP transcription factors have been implicated in embryonic stem cell pluripotency, and NR2F1 has been previously shown to interact with and enhance ERalpha activity through increasing its phosphorylation by MAPK. Therefore, overexpression of NR2F1 (and possibly NR2F2) may counteract the antagonistic effects of TAM and represent a novel pathway for TAM resistance in lobular and ductal ER+ breast cancers. Ongoing studies include gel electrophoresis to determine whether this overexpression is observed at the protein level and siRNA knockdown experiments to determine the impact of NR2F1 and NR2F2 on ERalpha phosphorylation and activity, TAM resistance, cell death, and overall survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4600.
Abstract 4601: XBP1 regulated function of c-MYC and BCL2 in antiestrogen resistance in breast cancer
Authors: McDaniel Lauren M. , Shajahan Ayesha N. , Clarke Robert 
Published: February 2011

Abstract
Breast cancer is one of the most prevalent types of cancer in the United States. In fact, one in eight women will be diagnosed with breast cancer at some point in their lifetime. Approximately, 70% of newly diagnosed cases of invasive breast cancer are estrogen receptor-α positive (ER+) and in these patients, the disease is often managed by antiestrogen therapy. A barrier in successfully treating some of these patients is their tumors’ ability to develop resistance to the antiestrogens. Previously, we have shown that one mechanism though which breast cancer cells become resistant to antiestrogens is by up-regulating the X-Binding protein 1 (XBP1). Specifically, the presence of the spliced form of XBP1, XBP1(S), confers resistance to breast cancer cells by inhibiting apoptosis. Overexpression of XBP1(S) in MCF-7 breast cancer cells also up-regulates the expression of c-MYC, a transcription factor that is involved in cell proliferation and cell survival, and BCL2, an anti-apoptotic molecule. c-MYC can confer partial resistance to the antiestrogen ICI 182, 780, and can cooperate with and/or be regulated by BCL2. We are investigating the role of XBP1 in regulating c-MYC and BCL2 in antiestrogen resistance. We hypothesize that co-inhibition of c-MYC and BCL2 will restore antiestrogen sensitivity to resistant breast cancer cells. We are using two MCF-7 variants: LCC9 cells that are an estrogen/antiestrogen resistant (ICI 182, 780 resistant and tamoxifen cross-resistant) and LCC1 cells that are estrogen/antiestrogen sensitive. Using small molecule inhibitors or lentiviral short hairpin RNA particles or we are specifically inhibiting our target molecules (c-MYC and BCL2) and testing the effects on antiestrogen responsiveness. Our preliminary data indicate that under basal condition, the antiestrogen resistant LCC9 cells are more sensitive to 10058-F4 (c-MYC inhibitor) and ABT-737 (BCL2 inhibitor) compared to LCC1 cells. Thus, in LCC9 cells, c-MYC and BCL2 clearly play important roles in cell survival. Our results will elucidate how XBP1 signals through c-MYC and BCL2 to confer endocrine resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4601.
Abstract 4602: Effect of estrogen receptor antagonistic drugs on expression and regulation of fatty acid synthase (FAS) in ER+ breast cancer cell lines
Authors: Atefi Mohammad S. , Zheng Cristina , Atefi Zahra , Slamon Dennis J. 
Published: February 2011

Abstract
Expression of estrogen receptor (ER) is detected in more than sixty percent of breast tumors. High levels of Fatty acid synthase (FAS) have been detected in aggressive breast cancers. Due to its high level of expression, FAS has been considered as a tumor marker and a therapeutic target. In normal rat liver, increase in expression of FAS requires glucose and a combination of hormones. Activity of FAS is indirectly regulated by the upstream signaling factor AMPK. AMPK is considered to be the main regulator of cellular metabolism. Upon activation, AMPK down regulates FAS activity and other ATP consuming pathways. In this study, we investigated the possible regulatory role of estrogen receptor (ER) signaling on FAS level and activity. In a panel of ER+ cell lines, very high levels of FAS expression was observed in the majority of the cell lines. The highest levels of FAS were in the ER+/HER2+ cell lines, HCC1419, BT474 and MDA-MB-361, respectively. However, in two other ER+/HER2+ cell lines, UACC732 and UACC812, the expression was similar to or even lower than the HER2 negative cell lines. Three HER2 negative cell lines in the panel also showed very high levels of FAS expression. Upon incubation of the cells in the absence of serum and phenol red condition, a general decrease in the FAS levels was observed that was more evident in HER2 negative cell lines. In the same condition, the effects of ER inhibitory drugs, fulvestrant and tamoxifen, on FAS and p-AMPKα levels were investigated. In ER+ cell lines that contain high levels of p-AKT, ER inhibitors did not affect levels of FAS and p-AMPKα. However, in some cell lines with lower levels of active AKT, tamoxifen and fulvestrant induced changes in FAS and p-AMPKα levels that were variable from cell line to cell line. In MCF-7 cell line, which is highly sensitive to ER inhibitors, both tamoxifen and fulvestrant induced lower FAS and higher p-AMPKα levels. Contrary to this observation, tamoxifen induced higher FAS and lower p-AMPKα levels in T-47D and KPL-1 cell lines. Fulvestrant induced a similar effect in ZR-75-1 cell line. This inducing effect of ER antagonists on FAS perhaps reflects one of the mechanisms that cause the elevation of blood lipids in post menopausal and tamoxifen treated women.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4602.
Abstract 4604: Roscovitine modulates ERα/ERβ ratio: A novel means to target hormonal therapy resistance
Authors: Nair Binoj Chandrasekharan , Morales Mary , Nair Hareesh Babu Bhaskaran , Vallabhaneni Sreeram , Li Rong , Tekmal Rajeshwar Rao , Vadlamudi Ratna K. 
Published: February 2011

Abstract
Current endocrine therapy for ER+ve breast cancer involves modulating ERα-pathway using either ERα-antagonists or aromatase inhibitors. Despite the positive effects, de novo and/or acquired resistance to endocrine therapies frequently occur. Although mechanisms for hormonal therapy resistance remains elusive, emerging data implicate ER-growth factor signaling cross talk, and alteration in ER subtypes as the major causes of resistance. Most downstream events in the resistance pathways converge upon modulation of cell cycle regulatory proteins; the most conspicuous of which is the activation of Cyclin Dependent Kinase 2 (CDK2) pathway. Roscovitine is one of the most frequently studied and used CDK2 inhibitor. In this study, we examined whether roscovitine confers tumor suppressive advantage to therapy resistant breast epithelial cells by inhibiting CDK functions using three therapy resistant model cells; (a) MCF-7-Tam (acquired Tamoxifen resistance model); (b) MCF-7-CA-LTLT (acquired Letrozole resistance model); (c) MCF-7-HER2 (ER-growth factor signaling cross talk model). Roscovitine at 10 μM concentration substantially reduced the growth of all three resistant model cells in cell proliferation and foci formation assays. FACS analysis revealed that roscovitine treatment increased proportion of cells in G2-M. To increase the drug efficacy, we have developed PLGA nanoparticles containing roscovitine and this mode of delivery significantly reduced the dosage needed to see the growth inhibitory effect in therapy resistant cells to 500 nM. To determine the mechanism, we have determined the relationship between CDK activity, expression of ERα, β subtypes, ER-coregulators, and expression of ER target genes in the presence or absence of roscovitine in resistant cells. Roscovitine substantially affected CDK2 activity and decreased cyclin A levels in the model cells. These studies also revealed an unexpected discovery that CDK inhibitor roscovitine has potential to alter the ratio of ER isoforms with preferential upregulation of ERβ expression with concomitant down regulation of ERα, its coregulators including AIB1 and PELP1. Since many advanced and therapy resistant tumors exhibit loss or reduced expression of ERβ, dual action of roscovitine will provide a novel drug to inhibit both CDKs and to increase the expression of tumor suppressor ERβ. Since deregulation of cell cycle machinery and estrogen receptor signaling contributes to resistance, roscovitine a drug that attacks both these pathways will serve as a double-edged sword to interfere with the resistance mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4604.
Abstract 4605: Combinatory use of synthetic and natural ER beta modulators in treating hormonal-therapy-resistant breast tumors
Authors: Ganapathy Manonmani , Nair Hareesh Babu Bhaskaran , Kirma Nameer , Krishnegowda Naveen , Vadlamudi Ratna , Mary Tagliaferri , Isaac Cohen , Tekmal Rajeshwar 
Published: February 2011

Abstract
Although systemic hormone therapies that either block local estrogen production by aromatase inhibitors (AI) such as letrozole or block actions of estrogen/ER actions by anti-estrogens like tamoxifen are well tolerated, the development of resistance to these agents is still a major concern. We have investigated whether treatment of letrozole resistant breast cancer cells with selective ER beta agonists (synthetic and of natural origin) in combination with letrozole restored sensitivity to this AI. We performed similar combination treatment of tamoxifen resistant cells with ER beta agonists and tamoxifen. To test whether combination therapy restores sensitivity to letrozole, we have treated letrozole resistant breast cancer cells LTLTca, derived from MCF-7-aromatase tumors resistant to letrozole] with either letrozole alone or with a combination of letrozole and DPN. Compared to single agents, combination treatment not only restored sensitivity to letrozole but also resulted in decreased cell proliferation and increased apoptosis as well as increased ERβ and decreased ERα levels in these cells. When we tested the growth of letrozole resistant breast tumors using a postmenopausal xenograft model, combination therapy not only restored sensitivity to letrozole but resulted in decreased tumor growth. Long term treatment using nanoparticle- encapsulated DPN and letrozole resulted in a significant and sustained decrease of tumor growth. On the other hand, nanoparticle-encapsulated letrozole treatment resulted in tumor resistance to therapy in13 weeks. In search for better and safer therapeutic modulators for ER, We have tested Liquiritigenein and Nyasol as selective natural ER beta agonists. Effects of these compounds on cell growth was tested in different breast cancer cells including MCF-7, MDA-MB-231, tamoxifen resistant MCF-7, and LTLT-Ca. In tamoxifen resistant MCF-7 breast cancer cells 15uM of liquiritigenin and Nyasol showed ∼70% and 90% of cell death, respectively. Different biological activities of liquiritigenin have been reported including anti-inflammatory activity. Combination of liquiritigenin and Nyasol with letrozole diminished cell growth in MCF-7, MCF-TAM, MCF-Aro and LTLT-Ca cells. Combination therapy using ER beta agonists like DPN, liquiritigenin and nyasol may offer superior response and restore the sensitivity to the current AI and anti-estrogens. Our study suggest a novel role of ER beta agonists as valuable therapeutic modulators to treat endocrine sensitive as well as resistant tumors. (Supported by NIH/NCI CA 750118 & P30 CA 54174, RRT)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4605.
Abstract 4614: Progesterone receptor and ErbB-2 crosstalk in breast cancer
Authors: Béguelin Wendy , Flaqué María C. Díaz , Cayrol Florencia , Proietti Cecilia J. , Rivas Martín A. , Tkach Mercedes , Charreau Eduardo H. , Schillaci Roxana , Elizalde Patricia V. 
Published: February 2011

Abstract
Progesterone receptor (PR) and ErbB-2, a member of the ErbBs family of receptor tyrosine kinases, play key roles in breast cancer development. Here, we identified a new mechanism of PR and ErbB-2 interaction in breast cancer cells. Our findings demonstrated that progestin stimulates the rapid activation of ErbB-2, its nuclear translocation, and a striking nuclear colocalization of ErbB-2 with signal transducer and activator of transcription 3 (Stat3) in human T47D breast cancer cells and C4HD cells, from a murine progestin-dependent mammary tumor. By using quantitative chromatin immunoprecipitation (ChIP) and sequential ChIP, we demonstrated that progestin induces the recruitment of Stat3 and ErbB-2 to Stat3 response elements (GAS sites) in the cyclin D1 promoter, which lacks ErbB-2 response elements (HAS sites). Through a series of experimental approaches including transient transfection with cyclin D1 promoter luciferase constructs and RNA interfering-reconstitution strategies employing functional ErbB-2 and Stat3 mutants, we revealed ErbB-2 role as a transcriptional coactivator of Stat3 in progestin-induced cyclin D1 promoter activation. Inhibition of ErbB-2 nuclear migration by transfection of breast cancer cells with the ErbB-2 nuclear localization domain mutant ErbB-2ΔNLS (Mol Cell Biol, 24: 11005-11018, 2005), which we here found that functions as a dominant negative inhibitor of endogenous ErbB-2 nuclear translocation, resulted in complete abrogation of progestin-induced in vitro and in vivo breast cancer growth. Our findings reveal a novel therapeutic intervention in PR- and ErbB-2- positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4614.
Abstract 4618: Effect of restoration of estrogen receptor-α (ER α) expression on drug sensitivities of gastric cancer cell lines
Authors: Woo In Sook , Kim Kyung Ae , Lee Kyu Sang , Byun Jae Ho , Han Chi Wha 
Published: February 2011

Abstract
Introduction: The significance of expression of estrogen receptor-α (ER α) and hormone manipulation is not established in gastric cancer. Positivity of ER α expression in gastric cancer ranges from 0-67%. We previously reported that promoter methylation of ER α is associated with loss of ER α in gastric cancer cell lines. The aim of this study was to examine the changes in sensitivity to tamoxifen and 5-fluorouracil (5-FU) after induction of ER α by the DNA methyltransferase-1(DNMT1) inhibitor 5′-aza-deoxycytidine (AZA) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA), following gene transfection of ER α into gastric cancer cell lines. Methods: ER α-negative gastric cancer cell lines including SNU-484, −638, and −71 were treated with AZA (10 μmol/L) and TSA (500 nmol/L). An ER α-encoding plasmid was transfected into an ER α-negative breast cancer cell line, MDA-MB-231, and gastric cancer cell lines. Cell proliferation was assayed in ER α-negative and -restored cell lines treated with tamoxifen (0, 1, 2.5, 5, 10, 15, 20, and 25 μM) or 5-FU (0, 0.02, 0.2, 2, 20, 200, and 1,000 μM). Results: Restoration of ER α expression in ER α-negative gastric cancer cell lines after treatment with AZA and TSA was confirmed by RT-PCR. Growth inhibition was more prominent in gastric cancer cell lines transfected with the ER α gene (with tamoxifen at a concentration of more than 15 μM) or treated with trichostatin (with tamoxifen at a concentration of more than 20 μM) than in ER α-negative gastric cancer cell lines. No differences in sensitivity to 5-FU were observed regardless of whether ER α was present or absent. Conclusion: The DNMT inhibitor AZA and the HDAC inhibitor TSA, together with tamoxifen, deserve further investigation as new targeted therapies in ER α-negative gastric cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4618.
Abstract 4621: Downregulation of Protein Kinase D1 in hepatocellular carcinoma (HCC): Potential as a diagnostic/prognostic molecular marker
Authors: Prakash Preethi , Freiz Matt , Bohlmeyer Teresa , Koch Micheal R.D , Chauhan Subhash C. , Jaggi Meena 
Published: February 2011

Abstract
OBJECTIVE: Protein Kinase D1 (PKD1) plays an important role in several cellular processes such as cell proliferation, oxidative stress signaling, adhesion and motility. PKD1 is of particular interest in diagnosis, prognosis and treatment of human diseases because of its enzymatic activity and susceptibility to successful therapeutic targeting. In our earlier study we have demonstrated suppression of PKD1 expression in advance stage prostrate cancer. This led us to analyze PKD1 expression patterns in various other cancer tissue samples.
MATERIAL AND METHODS: Tissue microarrays containing various cancer samples with corresponding normal tissues were used to investigate the expression profile of PKD1 using immunohistochemistry (Biocare Medical, Concord, CA). Further studies on PKD1 expression profile in hepatocellular carcinoma (HCC) were carried out using tissue microarray (TMA) containing HCC samples (n=70) with normal tissues (n=4) and a HCC TMA with hepatitis B viral history (HBV) containing HCC samples (n=100) with normal tissues (n=4) (AccuMax Array). Immunostaining was graded by two independent pathologists. Intensity and extent of staining scores were multiplied to obtain the composite score (CS) of each sample.
RESULT: Differential expression pattern of PKD1 was observed in brain, skin, lung, kidney, thyroid and ovarian cancer samples. Along with stomach and colon cancer, HCC samples showed a marked downregulation of PKD1 expression compared to their respective normal tissues. PKD1 expression profile was further evaluated in a large cohort of HCC samples. Overall, HCC samples showed a significant (p&gt;0.05) downregulation (Mean CS=6.0) of PKD1 expression compared to normal liver samples (Mean CS=11.4). Among cancer samples, advanced stage samples showed a relatively lower PKD1 expression (Mean CS=5.4) compared to early stage (Mean CS=6.6) HCC samples. Similarly, advance stage HCC samples with HBV showed a lower PKD1 expression (Mean CS=6.9) compared to early stage samples (Mean CS=9.6) and non neoplastic samples (Mean CS=12).
CONCLUSION: The results of this study suggest suppression of PKD1 expression in HCC. In view of the limitations of the available diagnostic/prognostic studies for detection of HCC, the aberrant expression of PKD1 may serve as a novel biomarker for the diagnosis/prognosis of hepatocellular carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4621.