bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-05-19: Modeling Cancer Recurrence and the Therapeutic Effect of Adjuvant Systemic Therapy
Authors: Ganesan S , Bhanot G , Boemo M , Lee JH 
Published: August 2014

Abstract
Despite complete surgical removal of early stage cancers, recurrence can occur at distant locations in time spans ranging from months to decades. This is due to the presence of disseminated cancer cells that can ultimately transition into active growth leading to recurrence. Systemic adjuvant therapy can decrease the incidence of distant relapse and lead to improved survival in some cancers. In this study, data on natural recurrence patterns of different breast cancer subtypes is used to build a probabilistic model of distant recurrence. The central hypothesis of this model is that after initial local therapy, a fraction of patients will have the presence of one or more disseminated dormant metastatic foci (DMF). The transition of DMF into actively growing metastatic foci (AMF) is described using a stochastic model. DMF of individual breast cancer subclasses each have a distinct probability per unit time of entering active growth. Fitting of this model to clinical trial data of early stage breast cancers treated with surgery alone demonstrates that DMF present in estrogen receptor negative (ER−) cancers and Luminal B cancer have greater probabilities of transition to active growth per unit time than Luminal A breast cancers. Clinical trial data were then used to determine the effect of adjuvant therapy on the dynamics of tumor recurrence. The data strongly support a model in which adjuvant chemotherapy works by eliminating only a fraction of DMF that have transitioned into AMF during the time of chemotherapy treatment. Thus short duration adjuvant chemotherapy would have greater efficacy in ER−, HER+ and Luminal B breast cancers, which have fast dynamics of recurrence, and little effect in Luminal A breast cancers with far slower dynamics of recurrence. Similarly, analysis of adjuvant hormonal therapy trial data, demonstrate that hormonal therapy also affects only DMF that transition into active growth during the period of hormonal therapy. This model can explain why extended duration therapy of up to 5 years is more effective than shorter duration of adjuvant hormonal therapy. Interestingly some adjuvant treatments, such as trastuzumab for HER2+ breast cancers, affect recurrence rates in a way that suggest that these interventions directly kill DMF. This model of tumor recurrence has several clinical implications that could inform future clinical trial design.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-19.
Abstract P1-05-22: Breast cancer cells that undergo an Epithelial-to-Mesenchymal transition co-opt LPP, a regulator of mesenchymal cell migration and invasion.
Authors: Ngan E , Northey JJ , Ursini-Siegel J , Siegel PM 
Published: August 2014

Abstract
Transforming Growth Factor β (TGFβ) promotes breast cancer cell metastasis to multiple sites, including the bone and lungs. TGFβ is a strong inducer of Epithelial-to-Mesenchymal transitions (EMT) and breast cancers that exhibit features of an EMT acquire stem cell-like characteristics, are highly aggressive, are resistant to therapy and are refractory to tumor suppressive processes. While TGFβ itself is non-oncogenic, it is a potent modifier of the malignant phenotype in breast cancer and is capable of enhancing the migration, invasion and metastasis of ErbB2 expressing breast cancer cells.
We have identified Lipoma Preferred Partner (LPP) as an indispensable regulator of TGFβ-induced migration and invasion of ErbB2 expressing breast cancer cells. LPP is ubiquitously expressed in smooth muscle cells where it mediates cell adhesion, migration and the formation of lamellipodial extensions. We hypothesize that breast cancer cells capable of undergoing an EMT can utilize novel mediators that are engaged in promoting the migration and invasion of mesenchymal cells. We propose that LPP is one such example, which promotes the migration and invasion of ErbB2 expressing breast cancer cells that have undergone a TGFβ-induced EMT.
We demonstrate that ErbB2 expressing breast cancer cells display significant increases in cell migration and invasion upon TGFβ stimulation, and such responses are dependent on LPP expression. We show that LPP re-localizes to focal adhesion complexes following TGFβ-induced EMT and it is a critical determinant in focal adhesion turnover. Furthermore, we determined that LPP targeting to focal adhesions through its LIM1 domain requires the cooperation of ErbB2 and TGFβ signaling pathways. Finally, we demonstrate that LPP promotes TGFβ-induced migration and invasion of ErbB2 expressing breast cancer cells through recruitment of α-Actinin, an actin cross-linking protein.
Overall, we have identified LPP as a novel mediator that integrates TGFβ and ErbB2 signaling to promote the migration and invasion of breast cancer cells that undergo an EMT. Our data reveal that breast cancer cells, which can transition from an epithelial to mesenchymal phenotype, can engage a regulator of mesenchymal cell migration and invasion.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-22.
Abstract P1-05-23: Blockade of mTORC1 decreases CXCR4-mediated migration and metastasis
Authors: Dillenburg Pilla P , Patel VT , Dorsam R , Masedunskas A , Amornphimoltham P , Weigert R , Molinolo A , Gutkind JS 
Published: August 2014

Abstract
Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein–coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell–derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies, including breast cancer. The downstream mechanisms of CXCR4-mediated migration are not fully elucidated. The study of the precise signaling pathways involved in cell migration and metastasis in each tumor type may help identify novel therapeutic targets for improving cancer therapy. Here we show that blockade of mTOR complex 1 (mTORC1) by Rapamycin or knocking down Raptor decreases CXCR4-Gαi mediated cell migration. Moreover, using a spontaneous lymph node metastasis model, we were able to show that pharmacological blockade of mTORC1 decreases lymph node metastasis in vivo. Taken together our data suggest that Rapamycin, a FDA-approved drug, could be beneficial to prevent tumor cells spreading from the primary tumor and metastasize. Molecular events underlying the effects of Rapamycin on CXCR4-induced migration will be presented.
This research was supported [in part] by the Intramural Research Program of the NIH, NIDCR.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-23.
Abstract P1-06-02: A newly angiogenic biomarker Vasohibin-1 expression in ductal carcinoma in situ of the breast.
Authors: Tamaki K , Tamaki N , Kamada Y , Uehara K , Miyashita M , Ishida T , Ohuchi N , Sasano H 
Published: August 2014

Abstract
Vasohibin-1 is a recently identified negative feedback regulator of angiogenesis induced by VEGF-A and bFGF. Our previous study was the first study demonstrating the status of vasohibin-1 in human breast lesions, which indicates that vasohibin-1 is associated with neovascularization and may especially play important roles in the regulation of intratumoral angiogenesis in human breast cancer. In this study, we first evaluated mRNA expression of vasohibin-1 and CD31 in 39 Japanese emale breast carcinoma specimens including 22 invasive ductal arcinoma (IDC) and 17 ductal carcinoma in situ (DCIS) using a real-time quantitative RT-PCR (QRT-PCR) with LightCycler system. Table shows the primer sequences used in real-time PCR in this study.

In addition, we also immunolocalized vasohibin-1 and CD31 and compared their immunoreactivity to nuclear grades and histological grades of 100 carcinoma cases (50 IDC and 50 DCIS). There were no statistically significant differences of CD31 mRNA expression and the number of CD31 positive vessels between DCIS and IDC (P = 0.250 and P = 0.191, respectively), whereas there was a statistically significant difference in vasohibin-1 mRNA expression and the number of vasohibin-1 positive vessels in DCIS and IDC (P = 0.022 and P &lt; 0.001, respectively). There was a significant positive correlation between vasohibin-1 mRNA level and Ki-67 labeling index in DCIS (r2 = 0.293, P &lt; 0.001). In addition, vasohibin-1 mRNA expression was correlated with high nuclear and histological grades in DCIS cases and a significant positive correlation was detected between the number of vasohibin-1 positive vessels and Ki-67 labeling index or nuclear grade or Van Nuys classification of carcinoma cells (P &lt;0.001, respectively). These results all indicate the possible correlation between aggressive biological features in DCIS including increased tumor cell proliferation and the status of neovascularization determined by vasohibin-1 immunoreactivity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-06-02.
Abstract P1-07-16: Liver derived epithelial cells as source of false positive circulating tumor cells in early breast cancer
Authors: Habets L , Körber W , Frenken B , Danaei M , Kusche M , Peisker U , Kroll T , Pachmann K 
Published: August 2014

Abstract
The MAINTRAC technique as introduced by our coworkers from Jena (RBC lysis, fluorometric detection and analysis on Olympius ScanR) detects more circulating epithelial cells than techniques using enrichment. Also cells with a low EPCAM expression are detected and not only the typical cells with bright expression found after immunomagnetic enrichment. The relative cheapness and reproducibility allows frequent monitoring during and after therapy Using 3 colour detection (EPCAMfitc, DAPI, Vimentin PE) living and dead circulating epithelial cells in EMT, or cells in EMT with stemcell markers (EPCAMfitc, Vimentin-PE, CD44PacBlue) can be detected. In early breast cancer (n = 135) cells can be found in 60% of patients and in 40% higher cell counts (&gt;100 ml are detectable. A control population(n = 100) showed low numbers in 98% (e.g (&lt;100 CECin 1 ml blood). Expression of the mesenchymal marker (vimentin) ranges between 10 and 40% with different expression. CD44 shows also a wide range of expression. Two main cell types can be distinguished: type 1 shows generalized but weaker expression patterns and a second type with very bright dotted expression. The clinical relevance of these subsets is not known and their behavior under therapy has not been analysed in depth yet. In advanced breast cancers high cell counts were detectable in most patients with a less agressive disease course. In the rapidly progressing unfavorable subtypes (TN and Her2+. HRneg) less or none cells were found. During crossvalidation in non cancer patients we found high cell numbers in several forms of liver affections (n = 108). The expression patterns of markers on these cells were not differing from those in cancer patients. So this same cell type merging EMT, stemcell an hypoxic stress markers is detectable in advanced and early breast cancer (n = 40) and in benign disease. These cells disappear or decrease after response to chemo or anti-hormonal therapy in cancer or antioxidant therapy in NAFLD. We believe that the evasion of these cells is driven by the same force in cancer as in non cancer conditions. We suggest that this are the wellknown hypoxic and hyperacidic conditions causing epithelial mesenchymal transition. Cancer cell hijack this functions occurring normally under these conditions to survive and to facilitate evasion. More comprehensive analysis (four colour analysis on the AMNIS Flowsight) is needed and should show differences in expression patterns of liver derived epithelial cells (LDEC) and real tumor derived epithelial cells (TDEC). Further clarification of these phenomena should give new insights of the biological events in early disease and the possibilities and reliability of “fluid biopsy”.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-16.
Abstract P1-07-18: Association between Bone Turnover Markers in patients with breast cancer and bone metastases on treatment with bisphosphonates (ZOMAR study)
Authors: Tusquets I , De la Piedra C , Manso L , Crespo C , Gómez P , Calvo L , Ruiz M , Martínez P , Perelló A , Antón A , Codes M , Margelí M , Murias A , Salvador J , Seguí MA , De Juán A , Gavilá J , Luque M , Pérez D , Zamora P , Arizcum A , Chacón JI , Heras L , Barnadas A 
Published: August 2014

Abstract
Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and consequently, levels of bone turnover markers (BTM). Increased levels of these biomarkers are related to the risk of skeletal-related events (SREs), disease progression and death. Treatment with bisphosphonates reduces the probability of SREs through osteoclastic activity inhibition. The aim of this study was to determine the relation between BTM, bone metastasis development and SREs, disease progression and death in patients with breast cancer (BC) and BMe.
Patients and methods: Observational, prospective and multicenter study. Patients with BC and BMe; no previous bone treatment in the last 6 months prior to study entry. Urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, UK) were determined at baseline (V0) and every 3 mo along 18 months (V6). Patients were treated with zoledronic acid (ZA) at inclusion and every 3–4 weeks.
Results: 234 patients with BC and BMe were analyzed. BTM results were available for 219 patients at basal visit (V0) and every 3 mo of treatment along 18 months (V6). Population basal characteristics (234 patients): mean age: 59.8 years; ER+: 80.3%; PR+: 64.9%; HER 2+: 18.3%. Patients with pathologic baseline levels were: 49.8% NTX, 39.6% αα-CTX and 83.4% BALP. A significant decrease was observed in BTM at V2 vs V0 after 6 months: 13.7%, 8.4% and 58.4% presented pathologic values of NTX, αα-CTX and BALP respectively. Normalized levels remained steady throughout 18 mo follow-up, finding significant decrease for each BMT for each time point except at V6 for αα-CTX. Regarding association between BTM and SREs, progression and exitus, a significant association was observed between pathologic levels of BTM throughout follow-up: with SRE at V3, V4 for NTX; with disease progression at V3, V4, V5, V6 for NTX, at V2 for αα–CTX and at each follow up visit for BALP; and with death at V1,4,5 for NTX, at V5 for αα–CTX and at V1,2,3,4,5 for BALP.
Conclusions: Addition of ZA to standard systemic therapy reduced BTM levels during the first 3 months of treatment and normalized levels remained steady throughout 18 months follow up except at Month 18 for αα-CTX. Pathological levels of BTM were significantly associated with SRE, disease progression and death.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-18.
Abstract P1-08-01: Effects Of An Allosteric AKT Inhibitor (MK2206) Administered With Or Without The Aromatase Inhibitor Vorozole In An ER+ Rat Mammary Cancer Model: Preventive And Therapeutic Effects
Authors: Lubet RA , Ellis MJ , Grubbs CJ 
Published: August 2014

Abstract
The AKT inhibitors appear to hold some promise with regards to inhibition of ER+ breast cancers which have relapsed. It has been hypothesized that the combination of an aromatase inhibitor plus an AKT inhibitor may be particularly effective. We, therefore, tested whether an allosteric AKT inhibitor (MK2206) alone or together with the aromatase inhibitor vorozole would be effective in a preventive and/or therapeutic setting. Female Sprague-Dawley rats were administered a single IV dose of methylnitrosourea (MNU) at 50 days of age. Beginning 5 days later, rats were administered the AKT inhibitor. In a preliminary study, two treatment regimens were employed: (1) dosing with inhibitor (100 mg/Kg BW/day, 7X/week) or (2) dosing with inhibitor (700 mg/Kg BW, 1X/week). These treatments minimally affected tumor multiplicity, but did significantly decrease tumor weights. We then examined the effects of combining the AKT inhibitor once weekly with a suboptimal dose of vorozole (0.12 mg/Kg BW/day) in a therapeutic setting. In a separate study, rats were treated with MNU and were allowed to develop their first palpable cancer. They were then treated with the combination of vorozole plus the AKT inhibitor or vehicle for 6 weeks. While tumors in vehicle treated rats grew an average of 600%, tumors treated with the inhibitor grew an average of only 95%; and, in fact, 5/12 showed a decrease in tumor size. Finally, we performed a similar combined study in a prevention setting. Dosing was: (a) AKT inhibitor (700 mg/Kg BW, 1X/week), (b) Vorozole (0.12 mg/Kg BW/day, 7X/week), (c) a plus b combined, and (d) vehicle. A, b, and c reduced tumor multiplicity by 26, 48 and 77%, respectively. Thus, combining an AKT inhibitor with an aromatase inhibitor showed synergy in prevention and treatment of ER+ tumors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-08-01.
Abstract P1-08-02: Gene expression changes in methylnitrosourea (MNU)-induced ER+ mammary cancers following short-term treatment of rats with SERMs (Tamoxifen and Arzoxifene)
Authors: Lubet R , Vedell P , Grubbs C , Bernard P , You M 
Published: August 2014

Abstract
SERMs have proven to be highly effective in both therapy and prevention of ER+ breast cancers. Tamoxifen has been the most commonly used SERM, but arzoxifene (another high- affinity competitive SERM agonist) showed strong activity in early clinical trials against ER+ breast cancer; although further development was discontinued. Both SERMs have shown a dose dependent effect on prevention and therapy of rat mammary tumors in the ER+ MNU model of cancer. Of interest, the doses required for prevention was significantly lower than the doses required for therapy. In the present study, rats bearing mammary cancers induced by MNU were treated with tamoxifen (0.66, 3.3, 20 and 100 ppm in diet) or arzoxifene (3.0 ppm in diet) for 5 days. Global gene expression analysis showed that more than 100 genes were down-regulated and more than 100 genes were up-regulated (p &lt; 0.05 and fold change &gt;1.5) in cancers treated with tamoxifen doses &gt; 3 ppm; and that many of these gene changes were dose dependent. The genes modulated by tamoxifen and arzoxifene were enriched in the cell cycle pathway that were related to chromosome condensation in prometaphase [including Aurora-A, Aurora-B, Bub1B, non-SMC condensing I complex, subunit H (BRRN1), Condensin, CAP-G, CAP-G/G2, CAP-H/H2, CAP-D2/D3, CAP-E, TOP2, Cyclin A, Cyclin B, CDK1, Histone H1 and inter-centromere protein (INCENP]. Employing a different set of tamoxifen treated samples, we were able to confirm that many of the same genes were modulated employing a quantitative RT-PCR assay. Finally, we will compare certain of the gene changes obtained in the animal model with gene changes observed in human neoadjuvant trials.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-08-02.
Abstract P1-09-01: Long-term effect of tamoxifen use on the risk of contralateral breast cancer
Authors: Mellemkjær L , Steding-Jessen M , Frederiksen K , Andersson M , Olsen JH 
Published: August 2014

Abstract
Background: Tamoxifen has been used widely in the treatment of breast cancer due to its beneficial effects on recurrences and mortality. Both randomized trials and observational studies give evidence that tamoxifen also reduces the incidence of contralateral breast cancer. The effect of tamoxifen seems to be present not only during treatment but also after termination of treatment, but the question is how long this effect lasts. Few studies have presented long-term follow-up data on risk of contralateral breast cancer after tamoxifen treatment.
Material and Methods: In the Danish Breast Cancer Cooperative Group (DBCG) Database, we identified 50,323 women who had undergone surgery for invasive breast cancer and who had received treatment according to DBCG guidelines during 1978–2007. Among these women, 16,319 were users of tamoxifen while 34,004 were non-users. Contralateral breast cancer cases were identified in the Danish Cancer Registry and in the DBCG Database through 2009. The incidence of contralateral breast cancer among users of tamoxifen was compared to that of non-users by estimating incidence rate ratios (IRRs) in Cox regression analyses with adjustment for age at first breast cancer diagnosis, calendar period at first breast cancer diagnosis, histology of first breast cancer, radiotherapy, chemotherapy and other endocrine treatments besides tamoxifen.
Results: During follow-up, 295 cases of contralateral breast cancer were observed among users of tamoxifen while 1,485 cases were observed among non-users resulting in an IRR of 0.82 (95% CI = 0.71–0.94) after adjustments. Further analyses will include calculation of IRRs for contralateral breast cancer by time since breast cancer diagnosis, duration of tamoxifen and time since cessation of tamoxifen as well as calculation of IRRs after restriction to estrogen receptor positive breast cancer patients. Results of these analyses will be presented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-01.