bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Targets of Insulin-Like Growth Factor-I Receptor (IGF-IR) Signaling and Their Potential Role in Breast Cancer.
Authors: Potter A. , Potter A. , Casa A. , Casa A. , Lee A. , Lee A. 
Published: December 2010

Abstract
BACKGROUND: Insulin-like Growth Factor-I Receptor (IGF-IR) has been implicated in a number of human tumors including breast cancer. IGF-IR is over-expressed and potentially hyper-phosphorylated in breast cancer. The specific gene targets of the IGF-IR signaling pathway, and the role of these genes in the development and progression breast cancer is not known.METHODS: MCF7B breast caner cells, and MCF10A immortalized mammary epithelial cells were treated with either serum-free medium or serum-free medium plus 100 ng/ml IGF-I for 3 hours and 24 hours. RNA was isolated and hybridized to U133A Affymetrix microarrays. Candidate genes were selected based on fold change and p-value. Q-RT-PCR was used to validate expression of potential candidate genes. 5,6-Dichlorobenzimidazole 1-β-D-ribofuranoside (DRB) was used (50µM) to block transcription. Cycloheximide (CHX) (20µg/mL) was used to block translation.RESULTS: Data from the microarray revealed 3673 and 3727 genes that were regulated by IGF-I treatment in MCF7B and MCF10A cells, respectively, at 3 hours. Various genes have been validated by Q-RT-PCR, and of these, Suppressor of Cytokine Signaling 2 (SOCS2) SOCS2 was repressed by IGF-I in MCF7B cells, but induced by IGF-I in MCF10A cells. The repression of SOCS2 by IGF-I was inhibited by pretreatment of MCF7B cells with a small molecule inhibitor of IGF-IR, but not by knockdown of IGF-IR by siRNA. This suggests that the repression of SOCS2 is specific to IGF-I signaling, but may be occurring through IGF-I stimulation of an alternate pathway other than IGF-IR. IGF-I doesn't alter levels of SOCS2 mRNA following blockade of transcription, suggesting that IGF-I does not have an effect on SOCS2 mRNA stability. Furthermore, IGF-I-mediated repression of SOCS2 does not require new protein synthesis, and is thus likely an immediate and direct response.CONCLUSION: SOCS2 is a candidate tumor suppressor gene in breast cancer, with loss of SOCS2 being related to cell proliferation and tumor growth. Here we show that SOCS2 is one of the gene targets of IGF-I signaling and is repressed by IGF-I stimulation in MCF7B breast cancer cells. Furthermore, the repression of SOCS2 by IGF-I appears to be via a direct inhibition of transcription. Together, this suggests that SOCS2 is a direct gene target of IGF-I signaling and that IGF-I repression of SOCS2 may be a crucial event that plays a role in driving the development or progression of breast cancer. Further studies are planned to determine how IGF-I affects SOCS2 function and the role of SOCS2 in breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4167.
The Growth Factor GP88 (Progranulin) Confers Aromatase Inhibitor Resistance to Breast Cancer Cells.
Authors: Serrero G. , Serrero G. , Brodie A. , Brodie A. , Sabnis G. , Macedo L. , Abrhale T. 
Published: December 2010

Abstract
The development of aromatase inhibitors has provided novel therapeutic strategies for post-menopausal patients with estrogen receptor positive (ER+) breast tumors. Aromatase inhibitors, such as letrozole, inhibit ER+ breast cancer cell growth by blocking the synthesis of estrogen by the enzyme aromatase in the tumor stroma. However, ER+ breast cancer cases can sometimes fail or cease to benefit from such therapy. Several mechanisms have been proposed for aromatase inhibitor resistance. Here, we investigate the role of the 88 kDa autocrine growth factor PC-Cell Derived Growth Factor, also known as GP88 or progranulin on the acquisition of aromatase inhibitors resistance by ER+ breast cancer cells. GP88 is the largest member of the epithelin-granulin family characterized by a unique cysteine rich motif. GP88 has been shown to play a role in breast tumorigenesis. GP88 expression increased in breast cancer cells in a positive correlation with tumorigenesis whereas inhibition of GP88 expression lead to a 98% reduction in tumor incidence and growth rate in vivo. Pathological studies of paraffin embedded breast cancer biopsies have shown that GP88 is expressed in infiltrating ductal carcinoma (IDC) in correlation with expression of parameters of poor prognosis but was independent from Her-2 expression. Most importantly, increased GP88 expression in ER+ IDC was associated with increased recurrence and decreased overall survival. The present study investigated the effect of GP88 on the proliferation and letrozole responsiveness of ER+ breast cancer cells that express high aromatase activity (MCF-7 CA and MCF-7 AC1 cells). For both cell types, GP88 added exogenously conferred letrozole resistance in a time and dose-dependent fashion. GP88 also stimulated survival and soft agar colony formation of MCF-7-CA and AC1 cells in the presence of letrozole. GP88 overexpressing cells displayed higher basal levels of phosphorylated ERK1/2 and AKT, both known to be activated in GP88 mitogenic signaling pathways. In addition, naturally letrozole resistant breast tumors displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. Treatment of these letrozole resistant cells with GP88 SiRNA lead to a dose dependent inhibition of proliferation and restoration of letrozole sensitivity indicating that GP88 is regulating the ability of the cells to respond to letrozole.These data show the importance of GP88 as a target for the development of diagnostic and therapeutic products for aromatase inhibitor resistant breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4171.
SOLTI-0701: A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo When Administered in Combination with Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer (BC).
Authors: Baselga J. , Roché H. , Costa F. , Getúlio Martins Segalla J. , Pinczowski H. , Ma Ciruelos E. , Cabral Filho S. , Gómez P. , Van Eyll B. ,   Grupo Español de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos
Published: December 2010

Abstract
INTRODUCTION: Sorafenib (SOR) is a potent multikinase inhibitor with anti-angiogenic and anti-proliferation activity. It is indicated for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. As a single agent, SOR has shown modest activity in patients with advanced BC. Here, we report results from one (SOLTI-0701) of four Phase 2b trials of sorafenib in combination with chemotherapy for advanced breast cancer.METHODS: SOLTI-0701 is a multinational, double-blind, randomized, placebo-controlled phase 2b study in patients with locally advanced or metastatic BC. Eligibility criteria included HER-2 negative tumors and &lt;2 prior chemo regimens for advanced/metastatic BC. Patients with active brain metastasis were excluded. Patients were randomized (1:1) to receive CAP (1000 mg/m2, orally, twice daily [BID], for 14 of every 21 days) with placebo (pl) or SOR (400 mg, orally, BID, continuously). Randomization is stratified by metastatic site (visceral vs nonvisceral). The primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, time to progression, response rate, response duration, safety, and QoL. Disease assessments occur every 6 weeks for the first 24 weeks of the study and then every 9 weeks thereafter until disease progression. Based on projected event and accrual rates, a sample size of 220 patients has been calculated. We estimate 120 PFS events within 17 months of study initiation. The study is registered at EudraCT (ID 2007-000290-32).RESULTS: Enrollment began in August 2007 and was completed in December 2008 with 229 patients randomized. Study findings demonstrated that the median PFS was extended in patients treated with SOR and CAP compared to patients receiving CAP and PL. These results were statistically significant (p=0.0006). The safety and tolerability of the combination did not show any new or unexpected toxicities. A subset analysis will be presented.CONCLUSION: The SOLTI-0701 study will provide important efficacy and safety data for the use of sorafenib in combination with oral chemotherapy for advanced breast cancer. These data will help us better understand the potential role for sorafenib in BC and if phase III trials are warranted.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 45.
Targeting Intrinsically-Resistant Breast Cancer Stem Cells with Gamma-Secretase Inhibitors.
Authors: Chang J. , Landis M. , Schott A. , Pavlick A. , Dobrolecki L. , Korkaya H. , Zhang X. , Froehlich A. , Rodriguez A. , Rimawi M. , Wicha M. , Lewis M. , Hayes D. 
Published: December 2010

Abstract
Background: We showed previously that tumorigenic, mammosphere-forming human breast cancer cells characterized by high CD44 and low or undetectable CD24 levels (CD44+/CD24-/low) are intrinsically resistant to conventional chemotherapy, and therefore may be responsible for cancer relapse. Our goal is identify novel drugs that selectively target these chemotherapy-resistant, tumor-initiating cells. Gene expression analysis of CD44+/CD24-/low cells vs. non-tumorigenic cells implicated the Notch, PI3K, and Hedgehog signaling pathways in regulating CD44+/CD24-/low cells. Thus, Notch, PI3K-AKT, and/or Hedgehog inhibitors may eliminate this unique subpopulation of cancer cells, either alone or in combination with chemotherapy, and could improve patient outcome. To test this hypothesis, we are carrying out a series of preclinical and clinical studies using a gamma-secretase inhibitor (GSI) to target the Notch pathway. Methods: For preclinical studies, stable xenograft lines were generated by transplantation of human tumor biopsy fragments into immunocompromised mice. Mice with tumors (n = 32, 150-300 mm3) were randomized to four treatment groups: 1) vehicle control, 2) chemotherapy: docetaxel 3) drug: GSI (MRK-003, Merck) or 4) combination: docetaxel + MRK-003. During treatment, mice were monitored for tumor volume and body weight. At the end of the treatment cycle, residual tumors were characterized by FACS for the percentage of CD44+/CD24-/low cells, as well as for mammosphere-forming efficiency (MSFE) and tumor-initiating capacity. In a complementary clinical trial, breast cancer biopsies taken before and after treatment with GSI (MK-0752, Merck) were characterized for expression of CD44, CD24, and ALDH by FACS and for MSFE. Results and Conclusions: In preclinical studies using two independent triple negative xenograft lines, Notch pathway inhibition reduced mammosphere formation but did not affect tumor volume, with no consistent change in marker expression by FACS. In patient samples, MSFE also declined after the first cycle of GSI/chemotherapy and remained low after subsequent cycles. This response corresponded with a stasis of metastatic growth during five cycles of treatment, but metastatic burden began to increase coincident with the sixth cycle of treatment. Marker analysis suggests that GSI treatment chemo-sensitizes a significant proportion of the otherwise chemo-resistant CD44+/CD24-/low cell population indicating that they are dependent on the Notch pathway for survival. The decrease of MSFE in both preclinical and clinical studies suggests that inhibition of the Notch pathway by GSI may reduce the number of tumorigenic cancer cells that would otherwise remain after chemotherapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 48.
Resident Macrophages Influence Stem Cell Activity in the Mammary Gland.
Authors: Gyorki D. , Lindeman G. , Visvader J. 
Published: December 2010

Abstract
Background: Increasing evidence suggests that macrophages play a role in the normal development of certain organs, including the breast1. Intriguingly, macrophages are often found in the stroma of breast tumours, where they may promote tumour growth and metastasis. The mechanism underpinning the requirement for macrophages during normal development may involve their interactions with mammary stem cells (MaSCs). Recently, a population enriched for MaSCs has been prospectively identified in mice2. We have used 2 approaches to determine whether macrophages are required for normal MaSC function.Methods and Results: The role of macrophages in mammary development was studied in mice with an inactivating recessive mutation in the CSF-1 gene (CSFop/op). MaSCs from CSFop/op mice exhibit significantly reduced clonogenicity in vitro with a reduction in colony size and number in CSFop/op mice. Transplantation assays confirmed a reduced regenerative capacity of the MaSCs derived from CSFop/op mice when transplanted into wild-type recipients. Furthermore, in reciprocal experiments, we found that a macrophage-deficient micro-environment does not support stem cell growth with an inability for wild-type stem cells to repopulate the fat pad of CSFop/op mice.To support these findings, an alternative strategy was used to eliminate the macrophages from the stem cell microenvironment by co-transplanting stem cells with liposomes containing clodronate or saline. Clodronate-containing liposomes are toxic to macrophages after ingestion. There was a greater than 80% impairment in stem cell repopulating frequency as well as a marked decrease in outgrowth potential when cotransplanted with clodronate-containing liposomes.Discussion: These studies indicate a major role for macrophages in supporting stem cell growth during mammary development. This may relate to a role in the stem cell niche. Understanding the mechanisms by which mammary stem cells interact with macrophages during mammary development will shed light on why macrophage infiltration in tumours portends a poor prognosis in breast cancer.1. Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002; 4:155-64.2. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006; 439:84-8.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 49.
Utilization of Serine-Derivatized Gadonanotubes as Magnetic Nanoprobes for Intracellular Labeling of MCF-7 Human Breast Cancer Cell.
Authors: Chan B. , Hassan A. , Hartman K. , Hartman K. , Ananta J. , Ananta J. , Mackeyev Y. , Hu L. , Pautler R. , Wilson L. , Wilson L. , Lee A. 
Published: December 2010

Abstract
The use of contrast agent enhances the image and gives a more accurate diagnosis by magnetic resonance imaging (MRI). However, safety of the patients with renal dysfunction raised the concern of increase in use. Comparing to the current clinical contrast agent gadopentetate dimeglumine (Gd-DTPA or Magnevist®), gadolinium-filled ultra-short carbon nanotubes (GNs) showed superior relaxivity. At different magnetic fields, GN increased relaxivity by 40-, 4.6- and 1.6-fold at magnetic fields of 1.5, 7 and 9.4T, respectively. More importantly, GN showed the ability in internalization that Gd-DTPA lacks. GN entered MCF-7 human breast cancer cells and allowed imaging of the cells by MRI. Detectable amount of gadolinium was found only in GN-treated MCF-7 cells by ICP-OES analysis. MRI of the kidney and liver showed GN was more dispersed suggesting that GN may be able to enter the interstitial space while Gd-DTPA was remained in the vasculature. Taken together, we found GN may be developed as a better contrast agent for MRI.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5005.
Non-Invasive Measurement of Pathological Heterogeneity of Cancer Tissues Using Water State Information from Diffuse Optical Spectroscopic Imaging.
Authors: Chung S. , Chung S. , Cerussi A. , Hsiang D. , Tromberg B. , Tromberg B. , Tromberg B. 
Published: December 2010

Abstract
Background: In our previous work, we have shown that biochemical tissue water state correlates with histopathological scores of breast cancer (R=-0.96). Based on the result, we extended our research to test whether the tissue water measurement can differentiate heterogeneous pathological structures of cancer tissues of different grades. Diffuse Optical Spectroscopic Imaging (DOSI) measures water molecular vibrational states associated with macro-molecular complexes in tissues such as proteins in a non-invasive way without compression of the breast. For DOSI measurements, a large region over breast tumors is scanned using a hand-held probe and spectral information on each point is spatially mapped to generate an image.Subjects and Methods: DOSI was employed to measure 19 primary cancers (18 IDC and 1 ILC). The spectral features of tissue water absorption from 935 nm to 998nm were compared to those of a pure water spectrum measured at body temperature in order to acquire the Bound Water Index (BWI: the residual between tissue and pure water spectra). In the spectroscopic images, the average and standard deviation of the pixels less than 20% of the range of the BWI in the image were calculated based on our previous finding that carcinoma tissues have lower BWI (more free water). The same parameters were calculated on normal tissues from the same patients in order to compare the tissue heterogeneity. The standard deviation was divided by the average value of each tissue type, and this value is communicated as a Heterogeneity Index (HI).Results: In our in vivo clinical studies, the cancer tissues showed 51% higher heterogeneity than the normal tissues (cancer HI: 0.046±0.018, normal HI: 0.024±0.018, p&lt;0.001). Furthermore, the low (N=4), medium (N=9) and high grade (N=6) tumors, defined by the Nottingham Bloom-Richardson histopathological scores (3-5: low, 6-7: med and 8-9: high), demonstrated increasing heterogeneity in the water disposition with the tumor grade. The medium and high grade tumors had 10.5 and 28% more heterogeneity than the low grade tumors in average (low grade HI: 0.041±0.015, med: 0.045±0.02 and high: 0.052±0.017).Discussion: The tissue water measurement using DOSI showed its ability to measure increased pathological heterogeneity in more invasive cancer tissues. This result supports our earlier finding that the BWI can report on histopathological grades of cancer tissues. These pathological properties were acquired in a completely non-invasive way with non-ionizing low power light. The results of this study suggest that the water state measurement using DOSI may be used as a non-invasive optical biopsy with high specificity.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5008.
Molecular Breast Imaging as a Cost Effective Diagnostic Tool for Breast Cancer.
Authors: Larsen A. , Hughes J. , Frazier T. 
Published: December 2010

Abstract
Introduction: Molecular breast imaging (MBI), also referred to as breast specific gamma imaging (BSGI), utilizes nuclear medicine imaging with technetium 99-sestamibi to demonstrate metabolic activity of breast tissue. A focused gamma camera is used to assist in detecting lesions concerning for malignancy based on abnormal radiotracer uptake. MBI is performed with the patient in a sitting position and requires less breast compression than mammography. MBI is safe for patients with implanted metallic devices and renal disease. Facility charge for MBI is approximately $600 vs. $2500 for magnetic resonance imaging (MRI).Methods: IRB approval was obtained prior to study initiation. Forty four (44) patients underwent MBI with technetium 99-sestamibi after mammography and or ultrasound detected abnormalities for which biopsy was recommended.Results: Forty four (44) women ranging in age from 28 to 82 (median age 52) were found to have abnormal mammogram and or ultrasound findings requiring image guided biopsy. Prior to biopsy, MBI was performed. Fifteen MBI's were interpreted as demonstrating areas concerning for malignancy. Nine of the 44 patients (20.5%) demonstrated malignancy on biopsy pathology. Eight of these nine patients had positive MBI findings concerning for malignancy (88.9%). The patient whose MBI did not demonstrate findings consistent with malignancy had two sites of DCIS. The positive predictive value of these results was 53.3% and the negative predictive value was 96.55%.Conclusions: MBI shows promise in evaluating patients with abnormal mammogram or ultrasound findings. MBI is available at a much lower cost than MRI ($600 vs. $2500), which would have resulted in savings of $83,600 in this study alone. MBI can be used in patients for whom MRI is not an option such as claustrophobic patients, patients with renal disease limiting use of gadolinium contrast and patients who for other reasons such as body habitus and implanted metallic devices are not candidates for MRI. Further studies evaluating MBI are warranted to determine what role it may play in providing additional diagnostic data about patients with abnormal mammograms or ultrasounds. The role of MBI in settings where breast MRI is not available, is not technically feasible or is not an option due to cost also warrants further evaluation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5014.
Correlation between Parameters of Optical Diffusion Imaging and Prognostic Factors of Breast Cancer.
Authors: Moon J. , Kim H. , Shin H. 
Published: December 2010

Abstract
Background: Total hemoglobin (HBT) and oxygen saturation (SO2) of optical diffusion imaging might be useful to predict extensive intraductal component (EIC) and lymphovascular invasion (LVI) in patients with breast cancer.To determine if the parameters of optical diffusion imaging correlate with the prognostic factors of breast cancer.Method and materials: A total of 95 patients who underwent surgery due to breast cancer were included in our study from March to October 2008. We obtained HBT, SO2 and synthesis diagnosis index (SDI) from optical diffusion imaging. Prognostic factors including estrogen receptor, progesterone receptor, HER-2/neu, HER-1, CK5/6, p53 status, LVI, EIC, lymph node metastasis and histologic grade were reviewed from pathologic report. We correlated HBT, SO2 and SDI on optical diffusion imaging with prognostic factors using Pearson correlation coefficient test.Result: Negative EIC showed correlation with low level of HBT and positive EIC showed correlation with high level of HBT (p=0.022). Negative LVI showed correlation with high level of SO2 and positive LVI showed correlation with low level of SO2 (p=0.038). Other prognostic factor shows no significant correlation with HBT and SO2. SDI shows no significant correlation with any prognostic factors.Conclusion: HBT and SO2 on optical diffusion imaging correlated with EIC and LVI, which enable prediction of EIC and LVI in patients with breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5018.