bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) Associated with Moderately Emetogenic (MEC) Chemotherapy in Patients with Breast Cancer.
Authors: Webb T. , Hardwick J. , Carides A. , Street J. 
Published: December 2010

Abstract
Purpose: Aprepitant was shown previously to be effective for prevention of CINV associated with MEC in breast cancer patients. A recent study (PN130) assessed aprepitant in patients with a variety of tumor types receiving a broad range of MEC regimens. A post-hoc subgroup analysis of patients with breast cancer was performed and results (nominal p-values) are reported.Methods: This randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to HEC or MEC agents, who received at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant 125 mg PO day 1 and 80 mg PO days 2-3, ondansetron 8 mg PO bid day 1, and dexamethasone 12 mg PO day 1) or an active control regimen (ondansetron 8 mg PO bid days 1-3 and dexamethasone 20 mg PO day 1). Primary and key secondary efficacy endpoints were proportions of patients with No Vomiting and Complete Response (no vomiting/no rescue medication use) respectively, during the overall phase (120 hours post-chemotherapy). Treatment group comparisons were based on a logistic regression model with terms for treatment, region, and gender.Results: Of 832 patients in the modified intent to treat population analyzed, 53% (n=439) had breast cancer. In the overall phase, significantly more patients in the aprepitant group achieved No Vomiting and Complete Response both overall and in the subgroup of patients with breast cancer (Table 1). The magnitude of the treatment group differences were similar to the differences observed in the entire study population. Similar trends were seen in the acute and delayed phase in both the overall population and the subgroup of patients with breast cancer. Results for additional endpoints are consistent with the data presented here. Adverse events were generally similar in the aprepitant and control groups. Aprepitant, n/m (%)Active control, n/m (%)No vomitingAll tumors324/425 (76.2)*252/406 (62.1) Breast cancer152/219 (69.4)*116/220 (52.7)Complete responseAll tumors292/425 (68.7)*229/407 (56.3) Breast cancer139/219 (63.5)*102/220 (46.4)n/m = patients with favorable response/patients included in subgroup; * p-value &lt; 0.001Conclusions: The aprepitant regimen provided superior efficacy over the control regimen for prevention of CINV for all patients receiving MEC. The benefit of aprepitant triple therapy in patients with breast cancer in this trial is in agreement with the results of a previous large-scale trial of aprepitant in this population. Control of CINV in breast cancer patients in this trial was consistently lower than in the overall population for all endpoints, demonstrating the importance of CINV prophylaxis in women with breast cancer undergoing MEC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1116.
Survivin Protects Breast Cancer Cells from DNA Damage during Mitosis.
Authors: Desplanques G. , Hulin P. , Juin P. , Barillé-Nion S. 
Published: December 2010

Abstract
Survivin has attracted considerable attention as a therapeutic target for anticancer strategies because of its dual role in regulating cell division and apoptosis, which are both involved in tumor development. Survivin associates with Aurora B kinase and inner centromere protein to form chromosomal passenger complex, dictating the localization of the complex and the activation of Aurora B kinase. Therefore, survivin plays an important role in mitotic spindle checkpoint. Survivin has been consistently identified as a risk-associated gene in various malignancies, carrying unfavorable implications for cancer prognosis, disease recurrence and abbreviated survival. Of note, together with other gene signatures, this information is now being used in the clinic for the risk assessment of breast cancer patients. Of particular interest, high Survivin levels have been consistently linked to inhibition of apoptosis induced by DNA damaging agents. We first confirmed in breast cancer cells that Survivin protected cells from cytotoxicity induced by the genotoxic agents cisplatin or doxorubicin. We further analyzed how Survivin might regulate DNA damage in these cells. We pointed out that Survivin knockdown by RNA interference led to mitotic arrest in breast cancer cells associated to DNA damage accumulation. Indeed phosphorylation on serine c-4 of the protein H2AX (gH2AX) and formation of (gH2AX) chromatin-associated foci were evidenced in Survivin-depleted cells in the absence of exogenous DNA damage. Moreover increase in comet parameters in single cell gel electrophoresis (alkaline comet assay) was also detected in these cells compared to control cells. Of note, this process was independent of apoptosis triggering since the pan-caspase inhibitor z-VAD-fmk did not abolish the DNA damage marks. Interestingly, Survivin knockdown had no impact on cell response to DNA damage, since (1) the increase in gH2AX foci was also associated with significant colocalization with both actors of DNA damage repair response Mre11 and Nbs1 and (2) the resolution of ionizing radiation-induced foci was similar in Survivin-depleted cells compared to control cells. These results demonstrate that Survivin depletion is indeed genotoxic in breast cancer cells but not involved in DNA repair pathways. Finally,we evidenced that taxol, that stabilizes microtubules in mitotic spindle and blocks cells cancer cells in mitosis, also induced DNA damage in breast cancer cells. Thus we conclude that prolonged mitosis induced by Survivin depletion contributes to DNA damage accumulation in breast cancer cells. We speculate that Survivin depletion in combination with genotoxic agents or inhibitors of DNA repair pathways may contribute to trigger apoptosis in these cells. Altogether, our results highlight the interest to use Survivin inhibitors in breast cancer therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1124.
Mechanisms of SLUG-Induced Drug Resistance Development in Breast Cancer Cells.
Authors: Mittal M. , Singh K. , Chaudhuri G. 
Published: December 2010

Abstract
Down regulation of vitamin D receptor and over-expression of cyclin D1 are often associated with breast cancers. Depending upon the genetic context of the breast cancer cells, these alterations also often lead to development of resistance of the breast cancer cells against drugs like vitamin D3, all-trans retinoic acid and tamoxifen. We report here that the metastasis promoter protein SLUG indirectly induces the elevation of cyclin D1 levels in human breast cancer cells by repressing vitamin D3 receptor (VDR) and ubiquitin conjugating enzyme UbE2D3 genes. SLUG over-expression repressed the mRNA and protein levels of VDR and UbE2D3 in SLUG-negative human breast cells whereas knockdown of SLUG in the SLUG-expressing human breast cells had the reverse effect. SLUG also E2-box-dependently inhibited the activity of VDR and UbE2D3 gene promoters. CtBP1 and HDAC1 are co-recruited at the VDR and UbE2D3 gene promoters with SLUG, further indicating that SLUG represses this gene through chromatin remodeling. Knockdown of UbE2D3 or VDR in the SLUG-negative human breast cells elevated the levels of cyclin D1 as well as the rates of proliferation/invasiveness of these cells. While SLUG over expression has no effect on tamoxifen-resistance of ER-negative breast cancer cells, it significantly decreases tamoxifen-sensitivity of ER-positive breast cancer cells. On the other hand, knockdown of VDR gene expression by SLUG increased the resistance of both ER-positive and ER-negative breast cancer cells to 1, 25(OH)2D3 and all-trans retinoic acid. Our data thus suggest that SLUG not only promotes metastatic development of breast cancer cells, but also conspire to the development of resistance of these cells against several anti-cancer compounds. Supported by the DOD-CDMRP IDEA Grant# W81XWH-06-1-0466 and the Susan G. Komen Breast Cancer Foundation grant# BCTR0707627 to GC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1128.
CYR61 Expression Promotes Taxol Resistance: A Molecular Link with the p53 in Breast.
Authors: Espinoza I. , Lupu R. 
Published: December 2010

Abstract
CYR61 render human breast cancer cells highly resistance to the microtubule-interfering agent Taxol, a drug of choice for the treatment of metastatic breast cancer. The angiogenic factor CYR61 and its receptor avβ3 are markedly up-regulated in very aggressive breast carcinomas. Integrin signaling has been shown to modulate cancer cell responses to chemotherapy agents. Thus, the signal transduction pathways initiated by integrin may be a potential target for inhibiting cell survival during cytotoxic drug exposure. However, the molecular mechanism for CYR61-induces cytoprotection still unknown. Our data demonstrates that functional blockade of avβ3 with a synthetic chemical peptidomimetic based upon the αvβ3 the RGD (Arg-Gly-Asp) motif, is specifically cytotoxic towards CYR61-overexpressing breast cancer cells and that pharmacological interference of the CYR61/αvβ3 interaction restores Taxol efficacy. This data suggests that a previously unrecognized CYR61/αvβ3-driven cellular signaling actively modulates cell growth, apoptosis and chemosensitivity. To better understand the mechanism by which CYR61 induces Taxol resistance, we studied a series of molecular events and reveal that CYR61 prevents Taxol induction of p53 accumulation, blocks p21WAF1/CIP1 overexpression, and furthermore we demonstrated that CYR61 induces JNK activation. These observations suggest that increased expression of CYR61 could promote a chemoresistance by suppressing a specific pro-apoptotic signaling while still given chemotherapeutic treatments to induce cell damage.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1139.
The Response of Breast Cancer Initiating Cells to Fractionated Radiation.
Authors: Lagadec C. , Vlashi E. , Della Donna L. , Pajonk F. 
Published: December 2010

Abstract
Recent experimental data provide evidence for a hierarchical structure of many solid cancers including breast cancer. Using surface markers, a small population of highly tumorigenic breast cancer initiating cells (CICs) has been prospectively identified, which exhibited a cancer stem cell phenotype, thus being able to self-renew and to give rise progeny of multiple different lineages of differentiated cells. We previously demonstrated that this population of cells was relatively resistant against ionizing radiation if compared to their non-tumorigenic counterparts. Furthermore, we reported that this population of CICs increased during the course of fractionated irradiation. The extent of the remaining self-renewing capacity and multi-lineage potency of these CICs after fractions of radiation is currently unknown. However, this information is crucial for evaluating the significance of radiation resistance of CICs.In the present study, we hypothesized that CICs not only survive fractions of ionizing more likely than their non-tumorigenic counterparts but also retain the CSC phenotype as defined by operational means and may even become more aggressive than populations of non-irradiated control CICs.Using CD24, CD44, ESA, and lack of proteasome function to identify breast cancer CICs we investigated their response to fractionated radiation and showed that CICs cells are more resistant to radiation (from 2Gy to 8x2Gy) than non-tumorigenic cells. At 2Gy, the stem cells population CD44high/CD24-/low in monolayer increased 3 times (from 0.25% at 0Gy to 0.74% at 2Gy). The analysis of CICs population after 8x2Gy demonstrated than the CICs containing population was not affected at higher total doses (0.25% at 0Gy and 0.28% at 8x2Gy). A sphere forming capacity assay demonstrated self-renewal capacity of the survivig CICs after irradiation (2Gy: +93% or 8x2Gy: +105%).Using low proteasome to identify stem cells and membrane labeling (PKH26) we analyzed the effect of fractionated irradiation treatment (0, 3Gy, 2x3Gy, 3x3Gy 4x3Gy and 5x3Gy) on CIC and non-tumorigenic cell proliferation. We demonstrated that CSCs irradiated with 3Gy or 2x3Gy lost the PHK26 dye faster than the control indicating recruitment of these cells into the pool of cycling cells (mean division of CSCs; 0Gy: 2.6, 3Gy or 2x3Gy: 3), while an treatment with 5x3Gy still enriched for CSCs but the reduction of proliferation rate of CSCs indicated that this enrichment is essentially due to their radioresistant phenotype (mean division; 5x3Gy: 1.9). Tumorigenicity of double positive and double negative cell was tested in limiting dilution assay using a mouse model (Rag2-/-IL2Rγc-/-).We conclude that radiation resistant CICs not only survive fractionated radiation but retain their CSC phenotype. This indicates that radiosensitizing CICs could be a reasonable approach to improve treatment outcome.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1153.
Blockade of Notch Signaling with Gamma-Secretase Inhibitors Induces Apoptosis in the Stem-Like Population of Breast Cancer Cells.
Authors: Foreman K. , Grudzien P. , Lo S. , Robinson P. , Albain K. , Strack P. , Miele L. 
Published: December 2010

Abstract
BACKGROUND: Numerous studies have identified stem-like cells, termed cancer stem cells (CSCs), in breast tumors and established cell lines. These self-renewing CSCs are believed to be responsible for breast cancer formation, progression and recurrence; therefore, a deeper understanding of the signaling pathways regulating their survival will benefit development of novel therapeutic strategies. Notch signaling, which is known to be dysregulated in breast cancer and has been implicated in mammary stem cell self-renewal, can be effectively blocked by gamma-secretase inhibitors (GSIs). While GSIs are currently in clinical trials for breast cancer, it is unclear how these compounds will affect CSCs or if CSCs from different breast cancer phenotypes (estrogen receptor-alpha (ER)-positive, ER negative, Her2/neu overexpressing) will be differentially affected. We previously reported that stem-like cells derived from the T47D breast cancer cell line showed elevated levels of Notch activity and Notch inhibition using GSIs or Notch decoy proteins abolished secondary mammosphere formation.METHODS: We have expanded our studies to breast cancer cell lines of different phenotypes (T47D-A18, T47D-C42, MCF7, SKBR3, BT474, MBA-MD231) and five primary clinical specimens. We studied expression of a panel of Notch pathway genes including Notch receptors, ligands and immediate downstream targets of Notch activation in CSCs and non-CSCs. We also determined the effect of Notch inhibition on secondary mammosphere formation (a measure of self-renewal) and clonogenicity. We evaluated cell death using TUNEL assays.RESULTS: We report that CSCs possess elevated levels of Notch activation compared to non-CSCs regardless of breast cancer phenotype or sample origin (cell culture or primary tumor). However, the specific Notch target genes most abundantly expressed vary depending on the cell line, and may suggest that CSC from different subtypes of breast cancer have different “Notch signatures”. Blockade of Notch signaling with a GSI abolished secondary mammosphere formation, eventually resulting in apoptosis, a finding that was consistent for ER-positive, ER-negative, and Her2/neu overexpressing cancer cells and primary tumor samples from heavily pre-treated, late-stage patients. Furthermore, GSIs blocked colony formation in soft agar.CONCLUSIONS: These novel findings support a role for Notch signaling in CSC self-renewal and proliferation, and they suggest Notch inhibition with agents currently in clinical development may prove beneficial in targeting CSCs in a wide variety of breast cancers.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1154.
Presence of Intratumoral Stem Cells in Breast Cancer Patients with or without BRCA Germline Mutations.
Authors: Singer C. , Zabkova P. , Pfeiler G. , Gschwantler-kaulich D. , Fink-Retter A. , Staudigl C. , Walter I. , Hudelist G. , Spiess A. , Kubista E. 
Published: December 2010

Abstract
Background:BRCA-1/2 germline mutations are responsible for early onset breast cancer with poor outcome. The underlying causes of the particularly malignant phenotype are not completely understood, but mammary stem cells appear to have a key role in this process.Materials and Methods: We have investigated the presence of mammary stem/progenitor cells in normal tissues and in tumor tissues obtained from women with and without BRCA1/2 germline mutations by utilizing ALDH-1 immunohistochemistry.Results: Isolated ALDH-1 positive cells were found in 15/18 (64%) of breast cancer samples from women with BRCA 1 or 2 mutations and in 33 /51 (65%) of matched sporadic breast cancer cases (p=0.5949, Chi Square test). While mammary stem cells were also detected in non-malignant breast lesions, only 41% of the tissues contained ALDH-1 positive cells (p=0.0371, Chi Square test). In patients with BRCA germline mutations ALDH-1 positive cells were more common in p53 positive (p=0.0028, Chi Square test) tumors, in high grade (p=0.0796), and in larger tumors (p=0.0604), while no such association was seen in sporadic cancer cases. In our patients, the expression of ALDH-1 positive cells in breast cancer was neither associated with disease-free and overall survival, nor time to metastasis.Conclusion: Breast cancers from BRCA mutation carriers do not harbour more ALHD-1 positive cells than sporadic tumors, and their more aggressive phenotype can thus not be explained by an increased stem cell pool. The presence of ALDH-1 in normal breast tissue suggests that additional factors determine the biological behaviour of mammary stem cells.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1156.
Novel Stably Transplantable Xenograft Models of Human Breast Cancer for Evaluation of Experimental Therapeutics.
Authors: Dobrolecki L. , Landis M. , Zhang X. , Huang J. , Lai Q. , Wong H. , Contreras A. , Chang J. , Lewis M. 
Published: December 2010

Abstract
In translational breast cancer research, our ability to evaluate clinical responses of human tumors to new therapeutic agents is severely limited experimentally. For example, it is not possible to evaluate the response of a single tumor to multiple candidate therapeutic agents. Conversely, the limited number of well-characterized in vivo preclinical human tumor models currently available precludes evaluation of multiple clinically relevant tumors with candidate therapeutic agents. These limitations severely impinge on our ability to develop and test novel therapeutic agents, particularly those that may target tumor-initiating “cancer stem cells”, which are relatively resistant to chemotherapy and radiation and may be responsible for disease recurrence and metastases.Historically, in vivo experimental therapeutic research has relied on either genetically engineered animal models, or “xenograft” transplantation models in which established human cancer cell lines are transplanted into immunocompromised host mice. However, each type of model has significant limitations. We sought to circumvent some of these limitations by propagating a cohort of human tumors as stably transplantable xenograft tissue lines grown in the absence of engineered or immortalized fibroblasts by transplanting clinical biopsies directly into the mammary fat pad of SCID/Beige immunocompromised mice (lacking B-cell, T-cell, and NK cell function) without intervening culture in vitro.Thus far, we have established 13 independent stably transplantable xenograft lines representing nine “triple-negative” (ER-PR-HER2-), two HER2+, and two ER+ breast cancers. Established xenograft lines show phenotypic similarity to the primary tumor with respect to histology and gene expression. Xenografts are being characterized genetically by whole genome sequencing as well as for the diversity of tumor-initiating cell types present. These models are proving useful for the evaluation of experimental therapeutics for their ability to inhibit tumor growth, and for their ability to target the subset cancer cells capable of regenerating tumors upon transplantation, with the goals of overcoming chemoresistance, preventing disease recurrence, and eliminating metastases.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1159.
The Impact of CD44+CD24- Cells on Non-Sentinel Axillary Lymph Node Metastases in Sentinel Node-Positive Breast Cancer.
Authors: Nogi H. , Kawase K. , Toriumi Y. , Fukushima H. , Suzuki M. , Uchida K. 
Published: December 2010

Abstract
Background: Although completion axillary lymph node dissection (CALND) is the standard for evaluating axillary status after identification of a positive sentinel lymph node (SLN) in breast cancer, approximately 30-60% of SLN-positive patients have negative non-SLN. It has been recently demonstrated that the putative breast cancer stem cells with CD44+CD24low/- phenotype are associated with self-renewal and tumorigenic potential. In this study, in order to explore such putative breast cancer stem cells in the SLN, we intended to retrospectively analyze expression of CD44+CD24low/- on metastatic tumor cells within SLN as a predictive factor for positive non-SLN (NSLN).Methods: We tested 271 patients for the SLNs by using serial sectioning and cytokeratin immunohistochemistry (IHC) and hematoxylin-eosin, and identified 67 patients who had a positive SLN biopsy and CALND. CD44 and CD24 expression was detected using IHC. Immunostaining for CD44 and CD24 interpreted as positive if at least 1% of tumor cells show distinct membranous staining. Univariate logistic regression techniques were used to assess significant associations.Results: Twenty-seven patients out of 67 patients (40%) had positive NSLN metastases. Six positive SLNs with micrometastases were not available for evaluation of CD24 and CD44 expression. Out of the 61 patients, 22 (36%), 47 (77%) and 28 (62%) patients had CD24-positive, CD44-positive and CD44+/CD24low/- metastatic tumor cells in SLN, respectively. Positive NSLN metastase was significantly associated with primary tumor size (P=0.004), negative CD24 expression (P=0.04), positive CD44 expression (P=0.04) and CD44+/CD24low/- (P=0.03).Conclusion: This is the first evidence for the existence of the putative stem-like phenotype within the SLN, which is significantly associated with positive NSLN, in early breast cancer patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1160.