bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-18-01: cMET Inhibitor and the Inhibition of Growth of Breast Cancer Cells in Bone Marrow Matrix Environment.
Authors: Ye L , Mason MD , Bramble P , Jiang WG 
Published: June 2012

Abstract
Background: Hepatocyte growth factor (HGF) is a cytokine that has a diverse but potential role in cancer including breast cancer. HGF, which action is mediated by its specific receptor, cMET, stimulate the aggressiveness of cancer cells by increasing the invasiveness and cellular migration. HGF is also a potent angiogenic factor. Small inhibitors to the HGF receptor are currently investigated in clinical trials of various cancers. In solid tumours which have potency of bone metastasis, HGF and particularly the HGF receptor, cMET, have been found to be particularly over-expressed in tumour cells metastasised to bones.
Materials and methods. A panel of breast cancer cell lines were used. Cell growth was determined using a colorimetic method. Cell adhesion and migration were investigated using a ECIS model. Bone matrix proteins were prepared from fresh bones. A small inhibitor to human cMET, PF02341066 was used in the present study in all the cell models.
Results. Depending on cell types, cancer cells tended to grow at a faster rate in bone marrow microenvironment than under normal conditions (12% higher for MDA MB 231 cells, for example). While PF02341066 have a concentration dependent effect on the growth of breast cancer, this effect became more marked when cells were growing in the bone marrow matrix. Breast cancer cells migrated rapidly in the presence of bone marrow environment, in comparison with controls. This was also inhibited by the cMET inhibitor. The study further showed that cells over-expressing a molecule linked to bone metastasis, namely ALCAM (1,2), responded more vigorously to cMET inhibitor in the matrix adhesion and cellular migration.
Conclusions. The present study has shown that the HGF receptor inhibitor has an inhibitory effect on breast cancer cells. This is particularly so when cells are grown in bone matrix microenvironment. It is concluded therefore that inhibitors to the HGF receptor may have a particular role in the management of bone metastasis in breast cancer.
References: 1. Davies S, Jiang WG. ALCAM, activated leukocyte cell adhesion molecule, influences the aggressive nature of breast cancer cells, a potential connection to bone metastasis. Anticancer Res. 2010, 30(4):1163–8; 2. King JA, et al. Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator. Breast Cancer Res. 2004;6(5):R478–87
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-01.
P4-01-10: The Role of the Steroid Receptor Coactivator SRC1 and Its Functional Partner HOXC11 in the Development of Endocrine Resistant Breast Cancer.
Authors: Walsh CA , McCartan D , Hill ADK , Young LS 
Published: June 2012

Abstract
Background: The steroid receptor coactivator; SRC1, has been well described in the development of endocrine resistant breast cancer. SRC1 associates with clinically aggressive tumours and promotion of distant metastasis. It directly interacts with the developmental transcription factor, HOXC11 and together they are found to strongly predict poor disease-free survival in breast cancer patients (hazard ratios: 5.79; P &lt; 0.0001). In this study, we investigate the mechanism of SRC1 and HOXC11 action in tumour adaptability and subsequent resistance to endocrine therapy.
Materials and Methods: Cells which are resistant to tamoxifen (LY2s) have enhanced SRC1 and HOXC11 mRNA and protein expression in comparison to their endocrine sensitive parent cells (MCF-7s). ChIP-sequencing data for SRC1- and HOXC11- DNA interactions in conjunction with DNA microarray and RNA-sequencing data identified potential signalling targets at play in the LY2 model of endocrine resistance. Real-time analysis and flow cytometry confirmed these interactions at a transcriptional and protein level. These observations were further confirmed in primary breast cancer cultures using flow cytometry.
Results: SRC1 and HOXC11 interactions are driven in tamoxifen treated LY2 resistant cells. Combined SRC1 ChIP-sequencing and expression array data analysed in conjunction with HOXC11 ChIP-sequencing and RNA-sequencing data reveal that the SRC1/HOXC11 transcriptional process can orchestrate the loss of luminal cell markers such as ERα, CD24 and PTCH1 whilst concomitantly upregulating mediators of tumourigenicity such as CD44 and MSI2. Primary breast cancer cultures confirm the loss of CD24 in tamoxifen resistant patients. In these patients, loss of CD24 was accompanied by loss of steroid receptor expression (ERα and PR) and by a gain of the basal marker CD44.
Discussion: Here, we describe a new signalling pathway where SRC1 and HOXC11 regulate two distinct but complementary mechanisms to drive tumour adaptability. Silencing of luminal cell markers and a concomitant increase in a basal cell phenotype has the potential to alter the survival mechanism of breast cancer cells to evade targeted therapy.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-10.
P4-02-04: Androgen Receptor (AR) Expression in a Cohort of Patients (pts) with Triple Negative Breast Cancer (TNBC).
Authors: Gucalp A , Gupta G , Patil S , Wen YH , Akram M , Brogi E , Powell SN , Ho AY , Hudis CA , Traina TA 
Published: June 2012

Abstract
Background
TNBC, defined by the absence of ER, PR, and HER2, is associated with higher risk of recurrence and BC-related mortality, earlier age at diagnosis, menarche, and 1st pregnancy, increased parity, higher BMI, and African-American/Hispanic race. TNBC is a heterogeneous group. Using gene expression analysis, our group described a subset of AR+ ER/PR- BC that exhibits androgen-dependent growth. In vitro studies confirmed the functional role of AR and showed that growth could be abrogated by antiandrogens.(Doane et al 2006) We translated this work into a phase II trial of bicalutamide in pts with AR+ ER/PR- metastatic BC (MBC). (NCT00468715) We now describe the prevalence and clinicopathological characteristics of AR+TNBC in primary disease in a single-institution retrospective cohort.
Methods: We identified 1,032 pts with resectable, TNBC (ER/PR&lt;1%; HER2&lt;2+/FISH&lt;2.2) who had surgery at MSKCC from 1998–2006. Exclusion criteria: neoadjuvant chemotherapy, prior radiation, inflammatory/MBC. IRB approval was obtained. We constructed tissue microarrays (TMA) from 210 primary tumors (&gt; 1 cm) with each tumor represented by three 0.6mm cores. AR was tested with DAKO antibody (Clone AR441; dilution 1:500). TMAs were digitized with a Mirax scanner. MetaMorph image analysis software was used to quantify the ratio of DAB staining to hematoxylin signal. A ratio &gt;1 SD above mean was defined as AR+. AR+ cores were manually reviewed; false positives due to core artifact were excluded. To evaluate clinicopathological variables and differences in recurrence-free survival (RFS) and overall survival (OS) by AR status we used chi-square/t-tests and Kaplan-Meier methods/log-rank test, respectively.
Results: 169 pts had adequate cores for image analysis/quantification of AR. 10% of pts tested AR+ (17/169). Median (med) followup: AR+=6 years (yr), AR-=5.6yr. Demographic/clinicopathological variables: Table 1 (ages in med yr). Overall med age=54yr (29-84). Adjuvant chemotherapy received: AR+ 82%, AR- 87%, p =0.40; 77% received anthracycline/taxane-based therapy. Med time to distant metastasis (DM)=2.1yr (0.2−6.2yr). We were unable to demonstrate a difference in 5yr RFS (69% vs. 77%; p=0.37) or OS (68% vs. 84%; p=0.25) between AR+ and AR- TNBC.

Conclusions: Consistent with our prospective study, AR is expressed in ∼10% of TNBC tumors in this retrospective cohort. The pts in our dataset may be older, postmenopausal, more likely to self-report white race and have T1-2/N0-1 BC. No statistically significant differences were observed in demographic/clinicopathological variables or survival outcomes between AR+ and AR- TNBC. Additional TMA data from our database will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-04.
P4-02-05: The Regulation of Artemin Signalling by IGF-1 in Mammary Carcinoma Cells.
Authors: Yip C , Liu D , Lobie PE , Perry JK 
Published: June 2012

Abstract
Artemin is a neurotrophic signalling factor which belongs to the glial-derived neurotrophic factor (GDNF) family of ligands. Artemin acts as a survival, proliferation and migration factor for a number of neurological cell types, by signalling through the RET (rearranged during transfection) receptor and, in most cases, the GDNF receptor (GFR)-a3 co-receptor. Recently, a number of published studies have implicated Artemin as a potential oncogene in several cell types, including mammary carcinoma cells. Other studies further indicate that Artemin may influence cancer progression and tamoxifen resistance in some breast cancers. Available clinical data has demonstrated that increased Artemin expression is correlated with decreased overall patient survival in breast cancer patients and a poor outcome in tamoxifen treated breast cancer patients. Here we investigate interaction between the Artemin and the insulin-like growth factor-1 (IGF-1) signal transduction pathways. Using mammary carcinoma cell lines, we demonstrate that IGF-1 treatment increases the endogenous expression of both Artemin and its endogenous receptors, RET and GFRa3. Semi-quantitative RT-PCR assays demonstrated that IGF-1 stimulated mRNA expression of Artemin as well as RET and GFRa3 in wild-type MCF-7 and ZR-75-1 cells in a time-dependent and dose-dependent manner. The same effect was not observed in wild-type T47D cells where IGF-1 did not increase Artemin mRNA expression.
We also demonstrated that forced expression of Artemin in MCF-7 cells consistently enhanced the response of these cells to IGF-1 in a number of cell function assays. Forced expression of Artemin significantly enhanced IGF-1-mediated stimulation of total cell number in MCF-7 cells. Consistent with this, Artemin enhanced IGF-1-mediated stimulation of S-phase entry and cell survival. In a soft agar assay, forced expression of Artemin also enhanced IGF-1-mediated stimulation of colony formation. Conversely, depletion of Artemin expression using siRNA abrogated the response to IGF-1 stimulation in MCF-7 cells. Artemin depletion significantly decreased IGF-1-stimulated increase in total cell number by decreasing IGF-1-stimulated cell proliferation and protection from apoptotic cell death. In addition, forced expression of Artemin in MCF-7 cells reduced cell sensitivity to the IGF-1 receptor small molecule inhibitor, AG1024. In conclusion, we have demonstrated that IGF-1 increases Artemin mRNA and protein expression in the breast cancer cell lines MCF-7 and ZR-75-1 and have identified potential cross-talk between the Artemin and IGF-1 signalling pathways in MCF-7 cells.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-05.
P4-02-06: Progesterone Receptor Expression Predicts Poor Outcome in Estrogen Receptor Positive, Lymph Node Negative Breast Cancer – A Population Based Study.
Authors: Purdie CA , Quinlan P , Jordan LB , Ashfield A , Baker L , Dewar JA , Thompson AM 
Published: June 2012

Abstract
Background: Estrogen receptor (ER) positive, lymph node (LN) negative breast cancer usually carries a good prognosis; endocrine therapy is often the only adjuvant treatment. However, a small proportion of such patients do badly (possibly representing those with luminal B cancers identified by gene expression profiling). A clinically applicable method for identifying this subgroup of poor prognosis ER+, LN- patients is required to offer them more intensive adjuvant therapy.
Material and methods: A consecutive, unselected series of 1072 new, operable breast cancer patients diagnosed between 2000 and 2004 was studied for ER and progesterone receptor (PR) expression, HER2 status and standard pathological and demographic parameters. ER and PR expression were scored on immunohistochemistry (IHC) on preoperative, diagnostic core biopsies using the “Quickscore” method. This ensured optimal fixation and tissue processing avoiding the variable fixation of resection specimens and the well-described sampling error of tissue micro-array (TMA) methodologies. PR expression is frequently heterogeneous resulting in false negative scores in at least 12% of cases by TMA analysis. HER2 status was assessed using IHC with dual color FISH for cases scoring 2+. Adjuvant therapy was prescribed using standard protocols; all patients with ER+ disease received adjuvant endocrine therapy. Follow up data were obtained from the oncology database, and the registrar of deaths for the date and cause of death. All deaths not attributable to breast cancer were censored at the date of death. Accordingly, the primary end-point was breast cancer-specific overall survival. Survival analysis was carried out by Kaplan-Meier survival curves analysed by the Log-Rank test. Multivariate analysis was carried out using Cox's regression.
Results: Overall, PR- cancers had a worse prognosis than PR+ (p&lt;10−12, Hazard Ratio 3.40), even in the ER+ (p=0.006, HR 1.86), LN- (p=10−8, HR=5.33) and LN+ (p=10−11, HR=3.26) sub-groups. In the ER+ LN- group, the absence of PR expression predicted worse prognosis (88% vs 96% 8 year survival, p=0.0003) with a hazard ratio of 3.75. This is considerably more significant than Ki67 IHC scoring reported for a similar group of patients in other studies (HR 2.22). Multivariate analysis demonstrated that PR expression was an independent prognostic variable second only to LN status and more powerful than ER.
Discussion: Patients with ER+, LN-, PR- breast cancers have a significantly worse prognosis than those with ER+, LN-, PR+ cancers. Unlike Ki67, PR IHC uses a simple, cost effective, standard methodology (as for ER) and should identify patients who may require chemotherapy in addition to endocrine therapy in this group of otherwise good prognosis patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-06.
P4-02-11: Insulin-Like Growth Factor I Promotes Estrogen Receptor Positive Breast Cancer Cell Proliferation, in Part, through CYP1A1 Signaling.
Authors: Rodriguez M , Becker M , Yee D , Potter D 
Published: June 2012

Abstract
Activation of the transmembrane tyrosine kinase insulin-like growth factor 1 receptor (IGF-1R) contributes to breast cancer progression. Nonetheless, the mechanisms by which the IGF-1R contributes to breast cancer progression need to be better characterized to further develop therapeutic strategies that target this pathway. It is known that cytochrome P450 monooxygenases synthesize metabolites from endogenous and exogenous sources that promote breast cancer proliferation. Here we propose that activity of the IGF-1R modulates the activity of CYP1A1 to promote breast cancer cell proliferation. We have found that IGF-IR activation by treatment with IGF1 (5nM ) for 4hrs induces cytochrome P450 1A1 (CYP1A1) mRNA levels in estrogen receptor (ER) positive line T47D-CO, but not ER negative line MDA-MB-231. Treatment with IGF1 promotes the proliferation of ER positive lines T47D-CO and MCF7. Interestingly, we found that treatment with IGF1 only partially compensates the growth-inhibition induced by CYP1A1 knock down by siRNA, suggesting that IGF1 requires CYP1A1 for full promotion of cell growth. These preliminary data suggest that IGF-1 signaling functions, in part, through CYP1A1 to promote ER positive breast cancer cell proliferation. The mechanism of IGF-1 signaling through CYP1A1 is novel and may represent an effector mechanism for IGF-1. Further understanding the role of CYP1A1 downstream of the IGF-1R may allow novel approaches for inhibition of breast cancer cell proliferation downstream of the IGF-1R.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-11.
P4-02-12: Plasma Estradiol Levels and Degree of Estrogen Receptor Positivity by Image Analysis in a Large Cohort of Breast Cancer Cases: Results from the Nurses' Health Study.
Authors: Collins LC , Frieling GW , Ahern TP , Hu R , Hankinson SE , Tamimi RM 
Published: June 2012

Abstract
Background
Breast cancer risk is strongly associated with endogenous reproductive hormones. There is also good evidence to suggest that endogenous estradiol levels are more strongly associated with the development of estrogen receptor (ER) positive breast cancers than with ER negative cancers. However, the degree of ER positivity in those cancers that develop is not yet established. Therefore, we sought to evaluate the proportion and intensity of tumor cells demonstrating ER positivity using image analysis in a large cohort of breast cancers for which we also had plasma estradiol levels.
Design: Tissue microarray (TMA) sections of breast cancers from women enrolled in the Nurses’ Health Study were immunostained for ER (1D5, Dako Corporation, Carpinteria, CA). Slides were then scanned using the ScanScope slide scanning system (Aperio Technologies Inc., Vista, CA) and ER staining was assessed for both intensity and percent of nuclei staining positively using a specific algorithm, Nuclear v9, which evaluates nuclear size, intensity, roundness, curvature, compactness, and elongation. Plasma samples were collected prior to the date of diagnosis for all women in the study and estradiol levels were determined by radioimmunoassay following extraction and celite column chromatography.
Result: Image analysis data for ER was available for 691 breast cancers. The mean percent of tumor cell positivity was approximately uniformly distributed, with a mean of 44.5%, (median=41.3%, max=99.6%). The proportion of tumor cells staining for ER from the TMA cores was positively associated with patient age (p&lt;0.0001), and postmenopausal status (p=0.008), while inversely associated with tumor grade (p&lt;0.0001). Among women with image analysis data for ER, plasma estradiol data were also available for 320 postmenopausal women. Estrogen receptor positivity (by proportion or intensity) did not vary according to plasma estradiol levels (p=0.17).

Conclusion: While high concentrations of plasma estradiol are more strongly associated with the development of estrogen receptor positive breast cancer versus estrogen receptor negative cancers, the degree of estrogen receptor positivity in the breast cancers that develop is not influenced by this variable.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-12.
P4-04-01: Identification of a Unique Mammary Cell Type Expressing Mesenchymal Markers, but Capable of Multilineage Epithelial Differentiation.
Authors: Landua JD , Lewis MT 
Published: June 2012

Abstract
We have identified a previously uncharacterized cell population within the epithelial compartment of the post-pubertal mouse mammary gland. These cells can be found as singlets or as like pairs in both the cap and body cell layer of terminal end buds (TEB) of developing ducts, and are ultimately localized in a suprabasal position distributed throughout the mature mammary ductal tree. In differentiated ducts, these cells typically extend long processes that contact multiple surrounding luminal epithelial and myoepithelial cells suggesting a function in cell-cell communication. In younger animals, identified cells do not express epithelial markers including the major cytokeratins (CK) 5, 6, 8, and 14, or E-cadherin, nor do they express myoepithelial cell markers such as smooth muscle actin or p63. However, in 20 week old non-parous females, these cells can give rise to epithelial cell types expressing CK 5, 6, 8, or 14. In transplantation assays, epithelial fragment and whole mammary gland transplantation did not indicate a major role in regenerative growth of mammary ducts. Transplantation of dissociated epithelial cells and wound-healing assays are in progress. Taken together, these observations suggest that this unique cell population possess stem cell-like features in that they are capable of self-renewal, and of giving rise to all major differentiated cell types within the mouse mammary gland.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-04-01.
P4-07-04: Nomogram Including Circulating Tumor Cells (CTC) Count before and during Chemotherapy for Individual Survival Prediction of Metastatic Breast Cancer Patients.
Authors: Bidard F-C , Hajage D , Bachelot T , Delaloge S , Brain E , Campone M , Wolp-Diniz R , Dieras V , Mathiot C , Asselain B , Pierga J-Y 
Published: June 2012

Abstract
Background
CTC count before a new line of treatment and CTC count early changes under chemotherapy have been reported as an independent prognostic marker in metastatic breast cancer in a recent pooled analysis in 841 pts (Liu M. ASCO 2011). The aim of this study was to build a prognostic tool including CTC and other parameters to assesse its predictive value for progression-free survival (PFS) and overall survival (OS).
Methods: Data from the IC 2006–04 study were used. This prospective multicentre study included 267 metastatic breast cancer patients treated by first line chemotherapy with or without targeted therapy, in whom appropriate pre-treatment prognostic variables (age, performance status, number of metastatic sites, disease-free interval, ER, PR and HER2 status, tumor grade, LDH, serum markers, CTC count by CellSearch technique before treatment and before cycle 2) were available for statistical analysis. We constructed a multivariate Cox regression model for PFS and OS prediction. A stepwise selection process was applied to achieve the most informative and parsimonious models. Performance was measured with the C-index statistic. Internal validation was performed using leave-two-out technique.
Results: Four nomograms have been obtained, in two clinical settings: at inclusion (before the start of any treatment) taking into account the initial CTC count, and during treatment (before cycle 2) taking into account CTC changes under treatment. Their accuracy was good for PFS and OS prediction, with C-index ranging from 0.72 to 0.88. Internal validations allow considering a good accuracy of the models in an external population.
Conclusion: These clinically relevant nomograms are a simple tool for a personalized prognostic assessment including CTC assessment. Validation on independent series of patients are ongoing.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-04.