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Supplementary Fig. S1 from Rapamycin inhibits multiple stages of c-Neu/ErbB2–induced tumor progression in a transgenic mouse model of HER2-positive breast cancer

PDF file - 46K, Patient Level Data. This table tabulates chemotherapy cycles received, response and DLT per patient.

Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy.Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies.Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.

PDF file - 39K, Probability of DLT. This table estimates the probability of dose-limiting toxicity by dose level

Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/phosphatidylinositol 3-kinase pathway and leads to the activation of mammalian target of rapamycin (mTOR), a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from mouse mammary tumor virus-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up-regulated (p85/phosphatidylinositol 3-kinase and p70S6 kinase) or down-regulated (eIF-4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of these mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. Whereas many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer show that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression. [Mol Cancer Ther 2007;6(8):2188–97]

Supplementary Methods, Tables 1-4, Figure Legends 1-9 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Table 10 � XLXS file 35K, Metastasis rates in xenograft lines

Supplementary Fig 1 � PDF file 42K, General design of the xenografting program

Supplementary Figure 2 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Figure 7 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Figure 1 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Fig 2 � PDF file 783K, Histology of unmatched xenograft lines

Supplementary Figure 4 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Table 3 � XLXS file 39K, Patient/xenograft biomarker comparison

Supplementary Fig 4 � PDF file 123K, Treatment response concordance with the tumor of origin

Supplementary Figure 9 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Table 2 � XLXS file 18K, STR Results

Using a syngeneic p53-null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified, by limiting dilution transplantation and in vitro mammosphere assay, a Lin−CD29HCD24H subpopulation of tumor-initiating cells. Upon subsequent transplantation, this subpopulation generated heterogeneous tumors that displayed properties similar to the primary tumor. Analysis of biomarkers suggests the Lin−CD29HCD24H subpopulation may have arisen from a bipotent mammary progenitor. Differentially expressed genes in the Lin−CD29HCD24H mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. These studies provide in vitro and in vivo data that support the cancer stem cell (CSC) hypothesis. Furthermore, this p53-null mouse mammary tumor model may allow us to identify new CSC markers and to test the functional importance of these markers. [Cancer Res 2008;68(12):4674–82]

Supplementary Figure 5 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Legends to Supplementary Figures - PDF file 65K, Legends to supplementary figures

Link for Supplementary Tables 4-7 � PDF file 39K, Table 4 - Patient Clinical Treatment Response; Table 5 - Frequency of Lung Metastasis in Xenograft Lines; Table 6 - Sequenom Analysis of SNPS in Xenografts; Table 7 - Xenograft Short Tandem Repeat (STR) Profile

Supplementary Figure 3 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Figure 6 from Identification of Tumor-Initiating Cells in a p53-Null Mouse Model of Breast Cancer

Supplementary Fig 3 � PDF file 31K, Demonstration of histological stability

Supplementary Table 8 � XLXS file 12K, Sequenom assays used

OBJECTIVE: Callous-unemotional (CU) traits are important characteristics for identifying severe patterns of conduct problems (CP). The current study focused on a) identifying subgroups of young children displaying a combination of CP and CU behaviors and b) examining the extent to which executive functioning (EF) and emotion regulation (ER) are associated with CU behaviors. METHOD: Participants included 249 preschoolers (N = 249, 78% boys, M(age) = 4.95 years; 81% Latino/Hispanic) referred to treatment due to externalizing behavior problems. CU behaviors and CP were measured via a combination of teacher/parent rating scales. A multi-method approach was used to measure EF and ER including parent/teacher rating scales, neuropsychological, and observational tasks. RESULTS: Poorer ER as rated by parents/teachers and observed was associated with greater levels of CU behaviors. Latent profile analyses identified three subgroups of children displaying a) low CU/low CP, b) moderate CU/moderate CP, and c) high CU/high CP. Children in the high CU/high CP group were rated as having significantly poorer rated ER compared to all other groups and poorer observed ER compared to the low CU/low CP group. Exploratory analyses found that children in the high CU/high CP group displayed marginally lower levels of rated ER but significantly better EF performance on standardized neuropsychological tasks compared to children in a low CU/high CP group. CONCLUSIONS: Children with higher levels of reported CU behaviors and CP display poorer ER yet may display relatively better EF performance compared to children with lower levels of CU behaviors and CP.

Mercury (Hg) deposition was reconstructed in sediment cores from lakes in two coastal U.S. National Parks: Acadia National Park (ANP) and Cape Cod National Seashore (CCNS), to fill an important spatial gap in Hg deposition records and to explore changing sources of Hg and processes affecting Hg accumulation in these coastal sites. Recent Hg deposition chronology was assessed using (1) a newly developed lead-210 (

Oxbow lakes are important stores for fine-grained sediment, which potentially makes them critical sinks for sediment-associated pollutants. We leverage an exhaustive public archive of coring data, supplemented by our data collection, to provide a quantitative assessment of the role of oxbows as off-channel sinks. We investigated loading trends of sediment-sorbed polychlorinated biphenyls (PCBs) within oxbows of the Housatonic River, an actively meandering river in western Massachusetts, USA. Our results reveal the efficiency of oxbows as sinks, with average PCB concentrations (14.8 ppm) that are nearly twice that of the surrounding floodplain (7.56 ppm). Even though the 5.83 km2 floodplain is the largest sink of PCB-laden material, storing as much as 14.1 t of PCBs or 2.42 g m−2, oxbows store more than 20% of all PCBs (3.63 t of PCBs or 11.2 g m−2) while making up just over 5% of the floodplain surface area. Nearly 85% of the oxbow storage of PCBs occurs within the first 50 m of floodplain, making clear the significance of regular oxbow production to the off-channel storage of sediment-associated pollutants.