bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B115: Excessive milk production during breast feeding prior to breast cancer diagnosis is associated with increased risk for early events
Authors: Gustbée Emma , Anesten Charlotte , Markkula Andrea , Simonsson Maria , Rose Carsten , Ingvar Christian , Jernstrom Helena 
Published: May 2015

Abstract
Background: Breast feeding is a known protective factor against breast cancer. Breast feeding duration is influenced by hormone levels, milk production, and lifestyle factors. We aimed to investigate how breast feeding duration and milk production affect tumor characteristics and risk for early breast cancer events in women who subsequently developed breast cancer.
Methods: Between 2002 and 2008, 634 primary breast cancer patients in Lund, Sweden, took part in an ongoing prospective cohort study. Data were extracted from preoperative questionnaires, pathology reports, patients' charts and Swedish registries from 592 patients without preoperative treatment.
Results: Breast feeding duration ≥12 months of the first child was associated with higher frequency of ER+/PgR+ tumors (P=0.02). Median follow-up time was 4.9 years. Higher risk for early events was observed for breast feeding duration of first child &gt;12 months (LogRank P=0.001), total breast feeding duration &gt;12 months (LogRank P=0.004), as well as ‘excessive milk production’ during breast feeding of the first child (LogRank P=0.003). Patients with ‘almost no milk production’ had no events. In a multivariable model including both ‘excessive milk production’ and breast feeding duration of the first child &gt;12 months, both were significantly associated with a two-fold risk for early events, adjusted HRs 2.19 (95% CI: 1.17-4.11) and 2.61 (1.06-6.38), respectively, adjusted for age, invasive tumor size, axillary lymph node involvement, ER and PgR status, age at first birth, time since last birth, smoking status, and BMI, while total breast feeding duration was not. ‘Excessive milk production’ was associated with a two-fold risk of early distant metastases, adjusted HR 2.41 (1.09-5.32), but not breast feeding duration.
Conclusion: ‘Excessive milk production’ during breast feeding was associated with higher risk for early events independent of tumor characteristics, while patients who reported ‘almost no milk production’ had no events. This finding stresses the need to consider host factors in the evaluation of prognostic markers.
Citation Format: Emma Gustbée, Charlotte Anesten, Andrea Markkula, Maria Simonsson, Carsten Rose, Christian Ingvar, Helena Jernstrom. Excessive milk production during breast feeding prior to breast cancer diagnosis is associated with increased risk for early events. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B115.
Abstract B117: Risk factors of second breast cancer among patients with ductal carcinoma in situ
Authors: Liu Ying , Colditz Graham 
Published: May 2015

Abstract
Background: Women with ductal carcinoma in situ (DCIS) are at increased risk of breast cancer in either ipsilateral or contralateral breasts. However, it is inconclusive about the factors predicting the risk of second breast cancer after DCIS.
Methods: We used US Surveillance, Epidemiology, and End Results data on women with first unilateral DCIS diagnosed between 1988 and 2009. Relative risks (RRs) were estimated using cox regression models to identify the factors associated with the risks of second DCIS and second invasive breast cancer (IBC).
Results: Of the 74,285 eligible DCIS patients, 6,140 (8.3%) had subsequent breast cancer during 8.5 years of follow-up (714 ipsilateral DCIS, 2,003 ipsilateral IBC, 997 contralateral DCIS, and 2,426 contralateral IBC). Patients &lt;50 years (RR=1.45; 95% confidence interval (CI), 1.29-1.64), black patients (RR=1.60; 95% CI, 1.39-1.83), patients with comedo DCIS (RR=1.19; 95% CI, 1.07-1.32), and patients with poorly differentiated DCIS (RR=1.45; 95% CI, 1.15-1.82) were more likely to develop ipsilateral breast cancer. Solid histologic type was more strongly associated with increased risk of ipsilateral IBC (RR=1.49; 95% CI, 1.12-1.99). The risk of contralateral breast cancer was increased among black women (RR=1.33; 95% CI, 1.16-1.52) and was decreased among young women and women with comedo DCIS, which was more obvious for contralateral IBC.
Conclusion: The risk factors were different for second breast cancer in the ipsilateral breast and in the contralateral breast. Improved follow-up of young patients, black patients, patients with poorly differentiated DCIS, and patients with comedo or solid DCIS may reduce the risk of second IBC. Further investigations are needed to identify molecular features of DCIS that predict risk of second breast cancer and/or mediate racial and age differences in second cancer risk.
Citation Format: Ying Liu, Graham Colditz. Risk factors of second breast cancer among patients with ductal carcinoma in situ. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B117.
Abstract IA05: Understanding estrogen receptor transcription in breast cancer
Authors: Carroll Jason S. 
Published: May 2015

Abstract
Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FOXA1 (HNF3a) was subsequently shown to bind to ~half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to explore ER and FoxA1 functional interactions in breast cancer, with a specific focus on changes in binding dynamics that occur during endocrine resistance. To this end, we have established transcription factor mapping approaches (ChIP-seq) in primary tumor material, to investigate differential ER/FoxA1 binding that occurs during tumor progression. We have functionally explored underlying factors that contribute to altered transcription factor binding and activity. In addition, we have recently established a method for rapid unbiased discovery of protein interactomes, which we have applied to discover ER and FoxA1 associated proteins. We find unexpected interactions between ER and additional nuclear receptors in ER+ breast cancer, which appear to be important modulators of cellular growth and endocrine response. These findings help delineate the complexes that influence ER transcriptional activity and ultimately impinge on tumor progression and drug sensitivity.
Citation Format: Jason S. Carroll. Understanding estrogen receptor transcription in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA05.
Abstract IA10: Using lineage tracing and clonal analysis to unravel mammary gland expansion and cancer initiation
Authors: Keymeulen Alexandra Van , Lee May Yin , Ousset Marielle , Blanpain Cédric 
Published: May 2015

Abstract
We developed novel lineage tracing approaches in mice to decipher the cellular hierarchy of the mammary epithelium during development, adulthood, pregnancy and lactation and to study the cell of origin of different types of breast cancers. Knowing that luminal cells specifically express the keratins K8 and K18, while myoepithelial cells express K5 an K14, we generated two inducible CRE recombinase (CREER) mice expressed in the luminal cells, under the control of K8 and K18 promoters to target luminal cells. To target myoepithelial cells, we used mice expressing the CREER under the control of K5 promoter, as well as the K14rtTA-TetOCRE mice. We demonstrated that the mammary gland initially develops from multipotent embryonic progenitors expressing K14, which give rise upon differentiation to both myoepithelial and luminal cells. However, during puberty and homeostasis, as well as during pregnancy and lactation, the expansion and the maintenance of luminal cells is ensured by the presence of luminal unipotent SCs, while the expansion and maintenance of myoepithelial cells is ensured by the presence of myoepithelial unipotent SCs, rather than being maintained by rare multipotent SCs. We also demonstrated that transplantation assays, while extremely informative about the differentiation potential of tissue specific SCs, can be misleading in extrapolating the differentiation potential of SCs under physiological conditions.
While the different genes implicated in inherited and sporadic breast cancers have been identified, the cellular origin of the different types of breast cancers remains elusive. Mutations in the cancer suppressor genes BRCA (BRCA1 and BRCA2) account for the majority of inherited breast cancers, and are associated with basal-like tumors. Oncogenic mutations in PIK3CA are found in 20 to 40% of invasive breast cancers and are associated with luminal tumors. To determine the cell of origin of breast cancers, we use the K8CREER mice to introduce oncogenic mutations specifically in luminal cells, while we use the K5CREER mice to introduce the mutations in basal cells. We target deletion of Brca1 and p53 to recapitulate basal-like breast cancers, while expression of the oncogene PIK3CA is used to recapitulate luminal-like breast cancers. Our results show that the differentiation of breast tumors can be misleading to extrapolate their cellular origin and that cell fate changes occur during breast cancer initiation.
Citation Format: Alexandra Van Keymeulen, May Yin Lee, Marielle Ousset, Cédric Blanpain. Using lineage tracing and clonal analysis to unravel mammary gland expansion and cancer initiation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA10.
Abstract A03: Immunoglobulin heavy chain usage in canine CLL
Authors: Burnett Robert , George Stacey , Mancha Serena , Bromerek Julia , Avery Anne 
Published: May 2015

Abstract
Canine B cell chronic lymphocytic leukemia resembles human CLL in presentation and clinical outcomes. The disease is indolent (median survival greater than 1000 days) and presents in older dogs (median age = 10.8 years). Major differences between the human and canine disease include immunophenotype (canine B cell CLL does not express CD5) and a gender ratio in the dog that is 1:1. Risk factors for canine B cell CLL have not been identified, but three breeds are more frequently represented amongst CLL cases than in the general population of dogs with confirmed or suspected lymphoproliferative disease of any type; Boxers, Shih-tsu dogs and English Bull dogs. Remarkably, the breed which most frequently develops a variety of lymphoproliferative disorders, the Golden Retriever, is virtually absent from the population of canine CLL patients. This breed predilection suggests that as in people, genetic factors contribute significantly to risk. We hypothesized that canine B cell CLL would be a useful model for uncovering genetic risk factors for the disease, and here we report initial characterization of this model by examining immunoglobulin V gene usage and mutation status. Our findings are: 1) 34% of dogs with CLL had unmutated IgVH genes, as defined by a difference of greater than 2% from the available germline sequence, 2) While the canine genome has 85 IgH V gene segments (43 pseudogenes, 42 functional genes), almost half (42%) of the CLL cases with unmutated IgH genes used a single V gene segment, VH41; Only 9% of non-neoplastic B cells utilize VH41, and 5% of CLL cases with mutated genes use VH41; 3) All animals of the Boxer breed had unmutated IgH genes; 4) canine VH35 was used in 29% of cases with somatic hypermutation, but was not found in unmutated CLL nor in the normal canine B cell repertoire. The striking breed association and restricted V gene usage suggest that certain dog breeds such as the Boxer could provide a useful model for investigation of genetic factors leading to B cell CLL in both humans and dogs.
Note: This abstract was not presented at the conference.
Citation Format: Robert Burnett, Stacey George, Serena Mancha, Julia Bromerek, Anne Avery. Immunoglobulin heavy chain usage in canine CLL. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A03.
Abstract A06: Interspecific recombination between orthologous human and mouse BAC clones in E. coli: Exploring scalable humanization of cancer-relevant genes in the mouse genome
Authors: Leidy-Davis Tiffany , Bergstrom David E. 
Published: May 2015

Abstract
Our interests lie in humanizing specific regions of the mouse genome using large segments of human DNA with extents of 10s to 100s of kilobase pairs. To that end, we have undertaken a series of projects to transfer large segments of human DNA, from human BAC clones, into the orthologous region of corresponding mouse BAC clones using— (1), traditional recombineering methods; (2), recombinase-mediated cassette exchange (RCME); and (3), a novel technology that we call trans- or trimolecular-recombineering. In each instance the goal is to place human DNA within the larger context of homologous BAC-derived mouse arms in E. coli.
Completed constructs will be used to drive homologous recombination in mouse embryonic stem (ES) cells with positive selection imparted at each end of the transferred human segment using dual, recombinase recognition site-flanked, selectable marker cassettes. Properly targeted ES cells will be used to develop viable mouse strains carrying the humanized segments. Selection cassettes will be removed by crossing to mouse strains with germline expression of the appropriate recombinases. All experiments have been designed to maintain a fixed genetic background from community-standard C57BL/6 strains. Our poster presentation details the specifics of our projects and describes progress to date.
This research is supported by National Cancer Institute Grant Number 5P30CA034196-28.
Citation Format: Tiffany Leidy-Davis, David E. Bergstrom. Interspecific recombination between orthologous human and mouse BAC clones in E. coli: Exploring scalable humanization of cancer-relevant genes in the mouse genome. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A06.
Abstract A27: BLM overexpression promotes tumorigenicity in an azoxymethane/dextran sulfate (AOM/DSS) murine model of intestinal cancer
Authors: Ebede Kenechi , McIlhatton Michael , Hankey William , Groden Joanna 
Published: May 2015

Abstract
The role of genomic instability in colorectal cancer susceptibility is well established by studies of hereditary non-polyposis colon cancer (HNPCC), its associated disruption of DNA mismatch repair, and other DNA repair deficiencies that predispose to colon cancer. DNA repair deficiency that results in loss of capacity to maintain the genome leads to increased mutation or chromosome instability that in turn increases tumor formation. In some recent experiments using mouse models of cancer, deletion of genomic housekeeping genes promoted tumorigenesis. The Blm gene encodes a RecQ helicase that represses aberrant homologous recombination. Previous experiments using ApcMin/+ mice showed that a heterozygous Blm mutation increased intestinal tumor formation and tumor dysplasia. Conversely, mice over-expressing BLM displayed more than a 50% reduction of intestinal tumor number compared to wild-type controls.
In order to isolate the effect of a Blm mutation on tumorigenicity, we used C57Bl/6 mice treated with azoxymethane and dextran sulfate to induce polyp formation. We predicted that mice with homozygous deletion of Blm would show an increase in tumor formation compared to wild-type mice, and transgenic mice over-expressing BLM would display fewer polyps. After treating our mice for 12 weeks and sacrificing them between 155 and 165 days of age, we found that mice with a complete deletion of Blm displayed a decrease in polyp formation compared to wild-type controls (3.0 polyps v. 5.5 polyps, p = 0.004). Transgenic mice over-expressing BLM in this model showed an increase in median polyp formation compared to wild-type controls (8.5 polyps v. 5.5 polyps, p = 0.01). Ongoing experiments will clarify the mechanism by which Blm promotes tumorigenesis in this mouse model of colon cancer.
Citation Format: Kenechi Ebede, Michael McIlhatton, William Hankey, Joanna Groden. BLM overexpression promotes tumorigenicity in an azoxymethane/dextran sulfate (AOM/DSS) murine model of intestinal cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A27.
Abstract A49: S6K1 promotes invasiveness of breast cancer cells in a novel model of triple-negative breast cancer metastasis
Authors: Khotskaya Yekaterina B. , Goverdhan Aarthi , Shen Jia , Sarvice Mariano Ponz , Chang Shih-Shin , Hsu Ming-Chuan , Wei Yongkun , Xia Weiya , Steeg Patricia , Yu Dihua , Hung Mien-Chie 
Published: May 2015

Abstract
Introduction: Breast cancer is the second-leading cause of oncology-related death in US women. Despite extensive research, over 30% of breast cancer patients develop metastatic disease, and metastases account for majority of breast cancer-associated morbidity and mortality. Of all invasive breast cancers, patients with tumors lacking expression of the Estrogen and Progesterone hormone Receptors and Human Epidermal growth factor Receptor 2 have the poorest clinical prognosis. These triple-negative tumors (TNBC) represent an aggressive form of the disease that is marked by an early-onset metastasis, a high tumor recurrence rate, and a low overall survival during the first three years post-diagnosis. However, few TNBC mouse models of metastasis currently exist.
Results: We noticed that a well-established MDA-MB-231 TNBC cell line produces rapid and extremely lytic bone lesions in lumbar, sacral and caudal vertebrae, and hind limbs in about 10% of animals injected intravenously. We biopsied one of these bone metastases and established a new metastatic MDA-MB-231-1566 cell line. Following an intravenous injection, MDA-MB-231-1566 cells produce early-onset metastasis to bone in up to 70% of animals with concurrent metastases to lungs, liver, and soft tissues. We demonstrate that 100% of animals injected with MDA-MB-231-1566 cells developed metastasis and had median survival of 60 days vs. 80 days in mice injected with the parental cell line. We also demonstrate that ribosomal protein S6 is highly phosphorylated on Ser235/236 in metastatic TNBC tumors, and that this phosphorylation is indicative of upstream S6 kinase (S6K) activity. Lastly, we provide evidence that targeting S6K with a highly specific inhibitor, PF-4708671, at sub-lethal doses inhibits cell migration without inducing cell death, and thus may provide a potent anti-metastatic adjuvant therapy approach.
Conclusion: We established a new model of rapid TNBC metastases to multiple organs following a simple intravenous injection. We believe this model provides a valuable tool for screening new therapeutics aimed to stop growth of metastases.
Citation Format: Yekaterina B. Khotskaya, Aarthi Goverdhan, Jia Shen, Mariano Ponz Sarvice, Shih-Shin Chang, Ming-Chuan Hsu, Yongkun Wei, Weiya Xia, Patricia Steeg, Dihua Yu, Mien-Chie Hung. S6K1 promotes invasiveness of breast cancer cells in a novel model of triple-negative breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A49.
Abstract B17: Stem-like cells selected by serial in vivo orthotopic passage of human pancreatic cancer cells
Authors: Metildi Cristina Angela , Kaushal Sharmeela , Hoffman Robert M. , Bouvet Michael 
Published: May 2015

Abstract
The aim of this study was to determine the stem-like properties of cancer cells after serial orthotopic passages in nude mice. Orthotopic mouse models of human pancreatic cancer cell lines were established by injecting 1x106 BxPC-3 RFP or Panc-1 GFP cells into the pancreas of nude mice. Cell lines were generated from primary pancreatic tumors. 1x106 cells of the passaged cell lines were orthotopically injected into another set of mice and this process was repeated until a decreased host-mouse survival plateau was reached. To evaluate stem-like characteristics, 1x106 cells of the parental (P0) and multiply passaged BxCP-3 RFP (P6) and Panc-1 GFP (P7) cell lines were orthotopically implanted into mice, which were followed until they were premorbid. In a second group of mice, the P0 and P6/7 lines were injected subcutaneously at difference cell concentrations (100, 500, 1000, 10000, 100000 cells) to determine the minimum cell number for tumor initiation. Additional orthotopic models were generated to evaluate differences in tumor progression and sensitivities to chemotherapeutic agent, gemcitabine. The P6 and P7 lines demonstrated more aggressive behavior with regard to tumorigenicity, tumor growth, metastasis, progression, and chemotherapy resistance. A significantly fewer number of P6 passaged cells of BxPC-3 (100 cells, p=0.02) and P7 Panc-1 (500 cells, p=0.005) were required for tumor initiation in mice by 6 weeks compared to their respective P0 lines. The P6/7 lines produced larger tumors at 6 weeks post implantation (p&lt;0.001). Mice harboring P6/7 tumors had a significantly greater degree of cachexia, more ascites, and greater metastatic tumor burden (p≤0.019) at 6 weeks. There was a significantly greater extent of metastatic disease in liver and lung samples from mice with tumors generated from P6/7 lines. The P6/7 lines' average time to metastasis and overall survival was reduced by more than one-half (p&lt;0.001). Both P6/7 lines were less sensitive to gemcitabine (p≤0.009). Thus, serial passaging allows for in vivo selection of more aggressive variants of the human pancreatic cancer cell lines BxPC-3 and Panc-1 which are also resistant to gemcitabine suggesting that stem-like cells are being selected.
Citation Format: Cristina Angela Metildi, Sharmeela Kaushal, Robert M. Hoffman, Michael Bouvet. Stem-like cells selected by serial in vivo orthotopic passage of human pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B17.