bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C95: Cancer health disparities in the U.S
Authors: Francoeur Jeri
Published: May 2016

Florida Breast Cancer Foundation and Susan G. Komen have similar missions in that they both are dedicated to ending breast cancer through advocacy, education and research and empowering others and ensuring quality care for all. Komen is at a global level whole Florida Breast Cancer Foundation is the State's breast cancer organization as it received the majority of its funds through the state license plate. This poster shows cancer disparities in the US, what they are, needs, and possible solutions. It will indicate the areas where more work is needed and hopefully will encourage others to become more involved through advocacy.

Citation Format: Jeri Francoeur. Cancer health disparities in the U.S. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C95.
Abstract C97: Destination Hope: Survivor support to enhance quality of life
Authors: Glosik Elizabeth (Betsy)
Published: May 2016

Destination Hope is a non-profit organization which provides uplifting and positive retreat support services for individuals in cancer treatment and their families. Each retreat is designed to be unique to the event space and address the specific needs of the participant group. Programs incorporate and teach healing and holistic approaches for self-care. Services are provided free of charge or with a minimal registration fee that may be waved for those who cannot afford it. This poster describes: retreat types, description of elements included in retreats, collaborative relationships with other non-profit providers, analysis of benefits obtained by participants, funding, participant recruitment, participant comments, and supporting evidence from research regarding the benefits of complementary and holistic therapies. Photographs of events are also included.

Citation Format: Elizabeth (Betsy) Glosik. Destination Hope: Survivor support to enhance quality of life. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C97.
Abstract IA10: Financial distress in patients with cancer: Contributing factors and potential solutions
Authors: Shankaran Veena
Published: May 2016

As the cost of cancer care in the United States continues to rise at an unprecedented rate, cancer patients are struggling to pay their share of the bill. Along with other measures of financial distress, cancer patients are 2.65 times more likely to file for bankruptcy than patients without cancer. Several recent reports suggest that individuals who face such financial challenges during treatment are more likely to report treatment non-adherence, poorer quality of life, and may suffer worse clinical outcomes. Despite an increasing awareness of “financial toxicity” among cancer patients, few oncology practices have processes in place to identify high out-of-pocket spending for cancer care and to provide assistance to patients struggling to pay for treatment or manage other life expenses. Given the rising cost of cancer care and its growing impact on cancer patients' financial health, the oncology community must be proactive in developing tools to steer vulnerable patients towards appropriate resources to reduce or prevent financial crisis. Such an approach may help to reduce disparities in treatment, adherence, and outcomes faced by cancer patients with limited financial reserves.

Addressing the patient-level financial burden of cancer care requires a multifaceted approach, including efforts at the policy level to negotiate pharmaceutical drug prices and improve structure of existing health insurance plans (e.g. Patient Protection and Affordable Care Act). At the health system and payer level, efforts to improve cost transparency may decrease waste and price variation while improving care quality.

At the patient and provider level, we propose several solutions that may also help to mitigate the financial burden of cancer treatment: 1) develop tools to track patient out-of-pocket costs and level of financial distress in real time; 2) develop strategies to align patients with available financial assistance resources from the time of diagnosis; 3) improve transparency about available effective treatment options and associated out-of-pocket costs to improve shared decision-making. In the era of widespread mobile phone and smartphone use across all racial and income groups, leveraging mobile technology to accomplish some of these goals is particularly appealing.

Citation Format: Veena Shankaran. Financial distress in patients with cancer: Contributing factors and potential solutions. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA10.
Abstract IA27: NCORP cancer care delivery research: A new opportunity for studying cancer disparities
Authors: Geiger Ann M.
Published: May 2016

Limitations in the availability and quality of cancer care have been associated with poor outcomes in medically underserved populations, independent of any biological factors. Differential access and care variation have been documented for many types of cancer and in all phases of care from screening through end-of-life. Patient-level interventions have had a modest impact on cancer disparities that arise in the process of care delivery. Challenges to further understanding and addressing care disparities include reliance on secondary use of data collected for other purposes (e.g., SEER-Medicare) and primary data collection in settings not reflective of the community (e.g., integrated delivery systems).

The NCI Community Oncology Research Program (NCORP) integrates a cancer care delivery component offering a new opportunity to study cancer disparities. Cancer care delivery research is defined as the development of “new and generalizable knowledge about the effectiveness, acceptability, cost, optimal delivery mode, active ingredients, and causal mechanisms that influence outcomes and affect the value of cancer care, across diverse settings and populations” (Kent EE et al. J Clin Oncol 2015; 33:2705-11). The ultimate goal is “evidence-based practice change [that will] improve clinical outcomes, enhance patient experiences, and optimize value” (Kent et al.). As is the case for all NCORP efforts, cancer care delivery research considers issues of the medically underserved, particularly racial/ethnic minorities and rural residents, a particular focus.

This presentation will describe cancer care delivery research and provide examples of cancer care disparities research that could be conducted within NCORP.

Citation Format: Ann M. Geiger. NCORP cancer care delivery research: A new opportunity for studying cancer disparities. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA27.
Abstract IA30: Approaching “precision disparities” in cervical cancer outcomes
Authors: Kobetz Erin , Rao R. Sunil , Yu Huilin , Miller Phillip , Garcia Ruslan , Hew Karina , Seay Julia
Published: May 2016

In the United States, Black women experience an increased risk of developing and dying from cervical cancer, primarily due to more advanced stage of disease at diagnosis. Black women tend to be diagnosed with later stage disease, when the prognosis for survival is poor, despite screening rates that meet and in some instances, exceed, those reported for white women. Thus, the observed survival difference between women of varying race/ethnicity may, in part, be biologically based. Research has identified key differences in the genotype, or strain, of Human Papillomavirus (HPV) associated with the cervical tumors of Black vs. white women with disease, and also found racial variability in the mutations expressed in other cancer sites. However, little is known about racial variability in epigenetic processes associated with disease onset and progression in cervical cancer, though there is increasing evidence that the methylation status of genes involved in carcinogenesis also varies by race. This is perhaps not surprising. Epigenetic alterations, such as DNA methylation, play an important role in various cellular functions, and are influenced by known cancer risk factors, including diet, tobacco, alcohol consumption, stress, and socio-environmental conditions, among others. Such factors vary across the population at large and between racial/ethnic groups, specifically. Blacks also have higher levels of methylation at birth relative to their white counterparts and, therefore, may be exposed to poorer outcomes, given the likely interaction between baseline biology and undue exposure to causal risk factors and risk conditions. We have developed a novel statistical approach, PRISM, which enables a more intuitive understanding of how biological factors interact with more upstream, social determinants to influence disease etiology and outcome. Using PRISM, we examine data from the publically available Cancer Genome Atlas (TCGA), and our ongoing work in Little Haiti, the largest enclave of Haitian settlement in the United States, to better understand the complex interplay between multilevel determinants of cervical cancer on disease survival.

Citation Format: Erin Kobetz, R. Sunil Rao, Huilin Yu, Phillip Miller, Ruslan Garcia, Karina Hew, Julia Seay. Approaching “precision disparities” in cervical cancer outcomes. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA30.
Abstract IA34: Evaluating methods of improving quality of life for cancer patients and improving acceptance of screening practices among cancer patients and their families
Authors: Manne Sharon L.
Published: May 2016

Dr. Manne will describe her ongoing R01 trial evaluating an intimacy-enhancing couples counseling versus a diet and exercise intervention and minimal care. She will also discuss the state of the science in quality of life for men with prostate cancer and their intimate relationships as well as important areas for future research.

Citation Format: Sharon L. Manne. Evaluating methods of improving quality of life for cancer patients and improving acceptance of screening practices among cancer patients and their families. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA34.
Abstract IA38: NCI MATCH: A national precision medicine trial – Conception, development, and adjustment
Authors: Conley Barbara A.
Published: May 2016

Precision medicine trials aim to provide evidence that targeting particular molecular abnormalities with specific treatment will result in better efficacy than current methods. While we know certain instances where the tumor type influences response to these agents, there are other instances where responses can be seen in various malignancies if they have the same molecular abnormality. Currently we do not know much about why some tumors or even most tumors will respond to a treatment, given the same mutation, and some do not. NCI MATCH is a national signal-finding trial for patients with solid tumors or lymphomas that have progressed after standard treatment. Patients register to a screening trial, have a biopsy of their tumor, and the tumor is analyzed by a targeted next generation sequencing panel and appropriate other molecular assays, and if an actionable mutation (one that can be addressed in MATCH) is found, the patient is evaluated for treatment with the appropriately matched drug(s). The goal is to seek a signal that targeting a molecular abnormality across tumors can be successful. The trial is open in hundreds of academic and community oncology sites through the National Clinical Trials Network of the NCI. The trial uses rules by which to assign a treatment, and depends on previous evidence that a given molecular abnormality is involved in cancer maintenance, and/or could result in a response to a given treatment. As most molecular abnormalities will occur in 10% or less of patients, the trial requires a large screening population and a large number of treatments within it. The trial is meant to change to accommodate new knowledge, and to expand as necessary to follow signals. We have an opportunity to study additional problems within NCI MATCH as well, such as molecular features of responders vs. non-responders, evaluation of genomic knowledge of patients, potential inheritable abnormalities that are also seen in the tumor, as well as study recruitment and retention issues within the trial. The talk will discuss the rules created for the trial, the initial early challenges, and some new areas of exploration going forward.

Citation Format: Barbara A. Conley. NCI MATCH: A national precision medicine trial – Conception, development, and adjustment. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA38.
Abstract A02: Stat3 plays a critical role in the establishment of immunosuppressive tumor microenvironment: Implications for tumor immunsurviellance and metastatic progression
Authors: Jones Laura M. , Broz Miranda , Ranger Jill , Ursini-Siegel Josie , Krummel Matthew , Muller William J.
Published: May 2016

Immune surveillance is thought to play a critical role in promoting the elimination of developing malignant lesions through activation of immune response. However, cancer cells eventually acquire the ability to escape immune surveillance by favoring recruitment of immune cell types that exert an inflammatory and immunosuppressive state. Despite the importance of immune surveillance, the molecular mechanisms that promote escape from immune remains poorly defined. Here we demonstrate that expression of the Stat3 transcription factor in the tumor epithelial is involved in promoting an immunosuppressive tumor microenvironment. To investigate the role of Stat3 in modulating the tumor immune-microenvironment, we ablated Stat3 in the tumor epithelia of an inducible PyV mT model of mammary tumor progression. Molecular and pathological analyses of tumor progression revealed that Stat3 deficient tumors were initially able to form hyperplastic and early adenoma–like lesions with no obvious impact on the proliferative or apoptotic status on these epithelial lesions. However, these early premalignant lesions completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Tumor regression was correlated with a massive infiltration of T lymphocytes and F4/80 positive macrophages into Stat3 deficient lesions. However focal Stat3 deficient mammary tumors escaped immune surveillance after a long latency period in a minority of the affected animals. Our data argue that tumor epithelial expression of Stat3 plays a critical role in promoting an immune suppressive tumor microenvironment .

Note: This abstract was not presented at the conference.

Citation Format: Laura M. Jones, Miranda Broz, Jill Ranger, Josie Ursini-Siegel, Matthew Krummel, William J. Muller. Stat3 plays a critical role in the establishment of immunosuppressive tumor microenvironment: Implications for tumor immunsurviellance and metastatic progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A02.
Abstract A15: Using genetic and pharmacological methods to explore role of the methyltransferase Ezh2 in mouse mammary tumorigenesis
Authors: Hirukawa Alison , Smith Harvey , Muller William
Published: May 2016

ErbB2 (HER2/Neu) is a receptor tyrosine kinase over expressed in 20-30% of primary human breast cancer cancer, and correlated with poor clinical outcome. However, the mechanisms through which ErbB2 contributes to tumorigenesis and poor patients prognosis is unclear. Over the last decade, several lines of evidence have demonstrated that the transformation of a normal epithelial cells to a malignant phenotype requires the accumulation of multiple genetics and epigenetic events, including post translational modifications of histones. Enhancer of Zeste 2 (Ezh2) is a polycomb group protein that, as a part of the PRC2 complex mediates gene silencing through tri-methylation of lysine 27 on histone 3 (H3K27me3). Interestingly, several clinical studies have reported EZH2 transcript and protein levels to be elevated in aggressive human breast carcinomas.

To investigate the requirement of Ezh2 in mouse mammary epithelial tumour initiation, we have crossed an Ezh2 conditional knock out mouse strain to a tetracycline inducible mammary epithelium specific Polyoma virus Middle T (PyVmT) transgenic mouse strain. The PyVmT model provides insight into how active receptor tyrosine kinase signalling can direct cellular transformation and its benefits include rapid tumour onset and well characterized disease progression, while the tetracycline-inducible systems allows for bypassing any developmental defects in the mammary gland due to Ezh2 ablation. Tumour onset in Ezh2 deficient mice are delayed(t50=135 days, n=15) compared to the wild type cohort (t50=63, n=28), and less multifocal in comparison to the wild type cohorts. End point tumours in Ezh2 deficient mice upregulate transcriptional signatures related to fibrosis and matrix remodelling, lipid biogenesis and cell cycle regulation. To compliment our genetic studies, we have also acquired a potent Ezh2 inhibitor, GSK126, to target the methyl transferase activity of Ezh2 in vivo and in vitro. Preliminary results indicate that the effect of global H3K27me3 loss is more pronounced during tumour initiation than tumour maintenance, and that in vivo effects of GSK-126 administration are likely mediated by the immune system.

Genetic studies will allow for us to dissect how Ezh2 (through H3K27me3) controls transcriptional programs during tumour initiation and maintenance. In combination with the development of a highly selective and potent Ezh2 inhibitor, GSK126, combined pharmaceutical studies and the use of genetic models will provide insight into potential therapeutic windows during disease progression.

Citation Format: Alison Hirukawa, Harvey Smith, William Muller. Using genetic and pharmacological methods to explore role of the methyltransferase Ezh2 in mouse mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A15.
Abstract A24: Age- and lineage-dependent gene expression is maintained by microenvironment imposed epigenetic states in human mammary epithelial cells
Authors: Miyano Masaru , Stoiber Marcus , Stampfer Martha , Brown Ben , LaBarge Mark A.
Published: May 2016

Normal healthy tissues show changing patterns of gene expression as a consequence of aging, and there is a functional cost to these changes that can be relevant to disease pathology. The most obvious age-related disease in breast is cancer, with the large majority of newly diagnosed breast cancer occuring in women over 50. We have shown that breast gene expression changes that occur with age have functional consequences in the epithelial progenitor and differentiated cells, i.e, a decline of the myoepithelial lineage, loss of luminal cell specificity, and accumulation of differentiation defective multipotent progenitor cells. We have hypothesized that these tissue-level changes make older epithelia more susceptible to transformation. Because gene expression patterns reflect the wiring and response diagrams of cells, it is of central importance to understand the origins of age-related transcriptomes. In our studies, early passage normal human mammary epithelial cells (HMEC) show age-dependent functional and molecular hallmarks consistent with in vivo, suggesting that the underlying gene expression patterns are metastable. DNA methylation is a stable, but malleable, form of epigenetic regulation that may underpin these biologically metastable states. Genome-wide analysis of primary epithelia was used to identify a set of genes that exhibit age- and lineage-specific expression that was inversely correlated with promoter CpG methylation. Chemical perturbation of DNA methylation in pre-menopausal HMEC resulted in a biochemical phenocopy of more advanced age. Tissue-mimetic cultures were used to demonstrate that lineage-specific gene expression and methylation in luminal cells were imposed by distinct microenvironments. Optimal maintenance of the luminal phenotype required direct contact with the apical surface of myoepithelial cells. Mimetic tissues built with HMEC that differed in chronological donor age revealed that age-dependent gene expression and methylation patterns are communicated between the two different lineages, as exposure of pre-menopausal luminal cells to a post-menopausal microenvironment imposed transcriptional patterns in luminal cells consistent with post-menopause. These data demonstrate that lineage- and age-dependent phenotypes in HMEC are maintained by microenvironment-imposed metastable epigenetic states.

Note: This abstract was not presented at the conference.

Citation Format: Masaru Miyano, Marcus Stoiber, Martha Stampfer, Ben Brown, Mark A. LaBarge. Age- and lineage-dependent gene expression is maintained by microenvironment imposed epigenetic states in human mammary epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A24.
Abstract A25: Cytometric atlas of the human breast: Comprehensive characterization reveals 12 distinct cell populations
Authors: Hines William Curtis , Carr Ambrose , Thi Kate , Wan Zhenmao , Pe'er Dana , Bissell Mina J.
Published: May 2016

Since formulation of the cellular theory in the early 19th century—relatively not so long ago—it has become universally recognized that tissues and organisms are formed and shaped by cells of many different types, all operating in beautiful harmony. Many mechanisms of this orchestration remain largely a mystery to this day, yet are important for us to understand if we are to fully comprehend fundamental processes in disease, especially one as formidable and perplexing as cancer. In the current era of progressive technological advances, many areas of biology are converging, and we now recognize and expect differences between cells, even among those of the same type, but whose origins rest in different tissues. Yet, many core tenets are being universally applied. The detailed cellular composition of tissues is clouded with uncertainty for many tissue types, and this includes the breast. To clarify the cell types in the breast and build a solid foundation for future work, we have meticulously examined a large collection of normal breast tissues, microscopically and by flow cytometry. We developed a complex antibody panel and rigorous gating strategy capable of objectively resolving and sorting each major cell type. We have sequenced mRNAs expressed by even the rarest of cell subpopulations and refined or developed methods for culturing each. This includes: several different luminal and epithelial fractions, myoepithelial cells, adipocytes, leukocytes, pericytes, erythrocytes, adipose-derived mesenchymal stem cells, and both lymphatic and vascular endothelial cells –12 different types in all. Future studies are aimed at developing heterotypic culture models using these cells, but also to use our new knowledge and experience to similarly explore heterogeneity of ductal carcinoma in situ (DCIS) and invasive breast cancers. We will present the development of this method and characterization to date of the sorted cell populations.

Citation Format: William Curtis Hines, Ambrose Carr, Kate Thi, Zhenmao Wan, Dana Pe'er, Mina J. Bissell. Cytometric atlas of the human breast: Comprehensive characterization reveals 12 distinct cell populations. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A25.
Abstract A29: Detection of ultra-rare mutations during breast stem cell tumor progression by Duplex Sequencing
Authors: Ahn Eun Hyun , Hirohata Kensen , Lee Seung Hyuk , Kim Joon Yup , Kohrn Brendan F. , Fox Edward J. , Chang Chia-Cheng , Loeb Lawrence A.
Published: May 2016

Most studies have mainly investigated clonal mutations due to the high background error frequencies of conventional next generation sequencing (NGS) methods. We have established a new method termed Duplex Sequencing (DS) that detects mutations with unprecedented accuracy and enables us to detect sub-clonal and rare mutations as well as clonal mutations. Using DS, we present our first genome-wide analysis of mitochondrial (mt) DNA mutations during the transformation of human normal breast stem cells to tumorigenic cells. We used a model system to dissect sequential steps in the progression of normal stem cells to tumorigenic cells. Significant differences have been found among normal stem cells, immortal cells, and tumorigenic cells. These cells differ in putative breast cancer stem cell (CSC) populations, mtDNA copy numbers, and the frequencies and types of mutations. We found that putative CSCs and mtDNA copy numbers increase as normal stem cells become tumorigenic cells. The vast majority of mutations identified in our study are stochastic (rare mutations) and the frequency of rare mutations is lower in transformed cells than in normal stem cells. This lower rare mutation load in transformed cells induces lower scores of predicted pathogenicity in transformed cells than in normal stem cells. C>T/G>A and A>G/T>C transitions are the major mutation types in normal stem cells, while only C>T/G>A are the major mutation types in transformed cells. Using DS, we detected a total of 1220 rare mutations and 678 of these variants have not been reported previously. The mtDNA mutation spectra of breast tumorigenic cells correlate with published nuclear DNA mutation signatures, which are found in the majority of tumors. We have identified mutations that can serve as potential biomarkers that indicate the different stages of breast carcinogenesis. These significant differences in mutation profiles could aid in characterizing different phenotypes between normal stem cells and transformed cells.

Citation Format: Eun Hyun Ahn, Kensen Hirohata, Seung Hyuk Lee, Joon Yup Kim, Brendan F. Kohrn, Edward J. Fox, Chia-Cheng Chang, Lawrence A. Loeb. Detection of ultra-rare mutations during breast stem cell tumor progression by Duplex Sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A29.
Abstract A39: A role for src kinase in estrogen receptor-positive breast cancer
Authors: Abdullah Christopher , Korkaya Hasan , Courtneidge Sara A.
Published: May 2016

Estrogen (E2) stimulation promotes proliferation in estrogen receptor-positive (ER+) breast cancer, which accounts for 60-75% of all breast cancer. E2 signals through the ER via three pathways: the classical genomic pathway involving transcriptional activation of the ER, crosstalk between ER and other transcription factors, and “non-genomic” signaling cascades, which do not involve the transcriptional activity of the ER. This “non-genomic” pathway likely involves Src family kinases (SFKs) and has been implicated in cell cycle progression in fibroblasts engineered to express the ER (Castoria 1999). While not typically amplified or mutationally activated in ER+ breast cancer, Src is hyperactive in most breast cancers.

To test whether SFK activity is required for G1/S cell cycle progression in breast cancer cells, we pretreated quiescent ER+ MCF7 or ZR75-1 cells with a selective SFK inhibitor (SU11333) prior to stimulation with E2. Inhibition of SFK activity blocked progression from G1 to S phase. Previous data from our laboratory has demonstrated that G1/S progression in response to peptide growth factor stimulation of quiescent fibroblasts is dependent upon SFK-mediated stabilization of myc mRNA (Bromann 2005). We therefore tested whether SFK activity also regulates myc expression in breast cancer cells. Our data suggest that SFK activity is required for accumulation of myc mRNA in quiescent MCF7s after E2 stimulation, and that E2 stimulated stabilization of myc mRNA is dependent on SFK activity. We are currently investigating the mechanism involved in stabilizing myc mRNA levels.

References:

Castoria et al. EMBO J, 1999

Bromann et al. JBC, 2005

Citation Format: Christopher Abdullah, Hasan Korkaya, Sara A. Courtneidge. A role for src kinase in estrogen receptor-positive breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A39.
Abstract B07: Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers
Authors: Williams Michelle M. , Lee Linus , Morrison Meghan M. , McKernan Courtney , Sanchez Violeta , Hicks Donna , Stricker Thomas , Cook Rebecca S.
Published: May 2016

In the context of cancer, the intrinsic apoptotic pathway is exploited to favor tumor cell survival through overexpression of anti-apoptotic Bcl-2 family members (Bcl-A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1). We investigated targeting of anti-apoptotic Bcl-2 proteins in a panel of human luminal breast cancer cell lines. Use of ABT-263, the Bcl-2/Bcl-xL/Bcl-w inhibitor, induced transient tumor cell killing and decreased tumor cell growth in only 1 of 4 cell lines in three dimensional (3D) cultures. Mcl-1 expression and activity were rapidly upregulated upon ABT-263 treatment, highlighting the compensatory nature of Mcl-1. In luminal breast cancers, Mcl-1 was the most frequently amplified anti-apoptotic Bcl-2 family member according to The Cancer Genome Atlas, while nearly 80% of the luminal breast tumor epithelium was positive for Mcl-1 in a tissue microarray. Thus, we hypothesized that Mcl-1 may be a dominant tumor cell survival factor in luminal breast cancers.

Use of the mTOR inhibitor RAD001 (everolimus) to target Mcl-1 indirectly decreased tumor cell growth and increased tumor cell killing in 3 of 4 cell lines, as well as WAP-Myc luminal mammary tumors, demonstrating the effectiveness of Mcl-1 as a therapeutic target in breast cancers. While Mcl-1 inhibition alone did not affect growth of T47D cells, robust growth inhibition and tumor cell killing were seen in all cell lines upon inhibition of Mcl-1 using RAD001 or a EIF4 complex inhibitor (4E1RCat) in combination with ABT-263, suggesting that the induction of Mcl-1 upon ABT-263 treatment may be supported by increased cap-dependent translation. These results demonstrate that the sensitivity of luminal breast cancers to ABT-263 is enhanced by Mcl-1 inhibition, warranting further investigation into inhibition of anti-apoptotic Bcl-2 family proteins, in particular Mcl-1, as a clinical strategy to improve survival of patients with luminal breast cancers.

Citation Format: Michelle M. Williams, Linus Lee, Meghan M. Morrison, Courtney McKernan, Violeta Sanchez, Donna Hicks, Thomas Stricker, Rebecca S. Cook. Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B07.
Abstract B15: Semaphorin 7a exerts pleiotropic effects to promote breast tumor progression
Authors: Black Sarah , Nelson Andrew , Gurule Natalia , Futscher Bernard , Lyons Traci R.
Published: May 2016

Understanding what drives breast tumor progression is of utmost importance for blocking tumor metastasis. We have identified that semaphorin 7a is a potent driver of breast tumor progression. Semaphorin 7a is a GPI membrane anchored protein that promotes attachment and spreading in multiple cell types. We observe that increased expression of SEMA7A occurs in ~45%human breast cancers and its upregulation is associated with decreased overall and distant metastasis free survival. In both in vitro and in vivo models, shRNA mediated silencing reveals roles for semaphorin 7a in the promotion of breast cancer cell growth, motility, and invasion as well as in lymphangiogenesis. Our studies also uncover a relationship between COX-2 and semaphorin 7a expression, and suggest that semaphorin 7a promotes tumor cell invasion on collagen and lymphangiogenesis via activation of β1-integrin receptor. Our results suggest that semaphorin 7a, may be novel target for blocking breast tumor progression.

Citation Format: Sarah Black, Andrew Nelson, Natalia Gurule, Bernard Futscher, Traci R. Lyons. Semaphorin 7a exerts pleiotropic effects to promote breast tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B15.
Abstract B60: The clinical significance and molecular features of the spatial tumor shapes in breast cancers
Authors: Moon Hyeong-Gon , Kim Namshin , Lee Minju , Moon HyunHye , Yoo Tae-Kyung , Lee Han-Byoel , Kim Jisun , Noh Dong-Young , Han Wonshik
Published: May 2016

Background: Each breast cancer has its unique spatial shape, but the clinical importance and the underlying mechanism for the three-dimensional tumor shapes are mostly unknown.

Methods: We collected the data on the three-dimensional tumor size and tumor volume data of invasive breast cancers from 2,250 patients who underwent surgery between Jan 2000 and Jul 2007. The degree of tumor eccentricity was estimated by using the difference between the spheroid tumor volume and ellipsoid tumor volume (spheroid-ellipsoid discrepancy, SED). In 39 patients, transcriptome and exome sequencing data obtained.

Results: Estimation of more accurate tumor burden by calculating ellipsoid tumor volumes did not improve the outcome prediction when compared to the traditional longest diameter measurement. However, the spatial tumor eccentricity, which was measured by SED, showed significant variation between the molecular subtypes of breast cancer. Additionally, the degree of tumor eccentricity was associated with well-known prognostic factors of breast cancer such as tumor size and lymph node metastasis. Transcriptome data from 39 patients showed significant association between genes involved in metal/ion binding, nucleotide binding, and extracellular matrix, and the degree of tumor eccentricity.

Conclusion: The present study validates the usefulness of the current tumor size method in determining tumor stages. Furthermore, we show that the tumors with high eccentricity are more likely to have aggressive tumor characteristics. Genes involved in the extracellular matrix remodeling are candidate regulators of the spatial tumor shapes in breast cancer.

Citation Format: Hyeong-Gon Moon, Namshin Kim, Minju Lee, HyunHye Moon, Tae-Kyung Yoo, Han-Byoel Lee, Jisun Kim, Dong-Young Noh, Wonshik Han. The clinical significance and molecular features of the spatial tumor shapes in breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B60.
Abstract B70: p16 and 9p21 deletion are largely unrelated but linked to unfavorable tumor phenotype in breast cancer
Authors: Lebok Patrick , Roming Magdalena , Kluth Martina , Koop Christina , Oezden Cansu , Taskin Brevian , Hussein Khakan , Lebeau Anette , Witzel Isabell , Mahner Sven , Geist Stefan , Paluchowski Peter , Wilke Christian , Heilenkoetter Uwe , Mueller Volkmar , Simon Ronald , Sauter Guido , Terracciano Luigi , Krech Rainer , Assen Albert von der , Burandt Eike
Published: May 2016

Overexpression of the p16 tumor suppressor, but also deletion of its gene locus 9p21, has been linked to unfavorable tumor phenotype and poor patient outcome in breast cancer. To better understand these seemingly contradictory observations, and the prognostic impact of p16 expression and 9p21 deletion in breast cancer, we analyzed a tissue microarray (TMA) with 2,197 breast cancers by fluorescence in-situ hybridization (FISH) using a CDKN2A-specific probe and by p16 immunohistochemistry. p16 immunostaining was typically uniform and considered weak in 25.6%, moderate in 7.1%, and strong in 12.7% of 1,684 analyzable cancers. Strong p16 staining was significantly linked to advanced tumor stage (p=0.0003), high-grade (p<0.0001), high tumor cell proliferation (p<0.0001), negative hormone receptor (ER/PR) status (p<0.0001 each), and shortened overall survival (p=0.0038). 9p21 deletion was found in 15.3% of 1,089 analyzable breast cancers, including 1.7% homozygous and 13.6% heterozygous deletions. 9p21 deletion was significantly linked to adverse tumor features, including high-grade (p<0.0001) and nodal positive cancers (p=0.0063), high cell proliferation (p<0.0001), negative hormone receptor (ER/PR) status (p≤0.0006), and HER2 amplification (p=0.0078). Patient outcome was also worse in p16 deleted than in undeleted cancers but this difference did not reach statistical significance (p=0,0720). p16 expression was absent in cancers harboring homozygous 9p21 deletions. However, a striking difference in p16 expression was not found between cancers with (59.2% p16 positive) and without heterozygous 9p21 deletion (51.3% p16 positive, p=0.0256). In conclusion, p16 expression is unrelated to 9p21 deletion, but both alterations are linked to aggressive breast cancer phenotype. High level p16 expression is a strong predictor of unfavorable disease course in breast cancer.

Citation Format: Patrick Lebok, Magdalena Roming, Martina Kluth, Christina Koop, Cansu Oezden, Brevian Taskin, Khakan Hussein, Anette Lebeau, Isabell Witzel, Sven Mahner, Stefan Geist, Peter Paluchowski, Christian Wilke, Uwe Heilenkoetter, Volkmar Mueller, Ronald Simon, Guido Sauter, Luigi Terracciano, Rainer Krech, Albert von der Assen, Eike Burandt. p16 and 9p21 deletion are largely unrelated but linked to unfavorable tumor phenotype in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B70.
Abstract IA11: Functional and clinical relevance of intratumor heterogeneity in breast cancer
Authors: Polyak Kornelia
Published: May 2016

Intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. We have analyzed cellular genetic and phenotypic heterogeneity in breast tumors using immune-FISH and found that higher pre-treatment genetic diversity predicts therapy resistance and distant metastases are the most diverse. In HER2+ tumors we detected startling heterogeneity for HER2 copy number gain and PIK3CA mutation using STAR-FISH, a novel method we developed, and determined that changes in the topologic distribution of cellular heterogeneity for these genetic alterations during neoadjuvant chemotherapy predicts long-term clinical outcome.

We have also developed experimental models of subclonal heterogeneity and shown that polyclonal tumors grow faster and are more metastatic than monoclonal ones, a tumor-driver clone can be a minor subpopulation acting via non-cell-autonomous mechanisms, a dominant clone can outcompete the tumor-driver minor clone leading to tumor collapse, and that cancer therapies intensify clonal competition potentially leading to inadvertent acceleration of disease progression.

Our results emphasize the need to study tumors as a whole and to understand the properties of cancer cell populations that compose tumors and interactions among them to be able to predict tumor evolution during disease progression and cancer therapies.

Citation Format: Kornelia Polyak. Functional and clinical relevance of intratumor heterogeneity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA11.
Abstract IA24: A stem cell program in early human metastatic breast cancer cells
Authors: Lawson Devon , Kessenbrock Kai , Werb Zena
Published: May 2016

Metastasis is the process that leads to the poor prognosis in breast cancer. Understanding the processes involved in the initiation and progression of metastasis is critical for developing new preventative and therapeutic strategies. One hypothesis states that metastases arise from rare tumor cells that resemble stem cells in their ability to initiate and propagate tumors. In this study we used single-cell analysis to demonstrate that the initial disseminating metastatic cells resemble stem cells in their gene expression. We exploited patient-derived xenograft (PDX) models of human breast cancer to analyze metastatic cells in peripheral tissues. We developed a highly sensitive FACS-based assay to isolate and enumerate these metastatic cells. The primary tumor cells were heterogeneous and expressed high levels of luminal differentiation genes The metastatic cells from tissues with a low metastatic burden showed increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes and differential expression of genes depending on the peripheral tissue. In contrast, in macrometastases, the cells were similar to primary tumor cells. The stem cell-like metastatic cells from low-burden tissues had significant tumor-initiating capacity upon transplantation, and differentiated to produce cancer cells with luminal gene expression. As the metastases progressed to a high metastatic burden the tumor cells showed increased expression of cMYC and proliferation-related genes. Our studies suggest that metastases are initiated by cells with stem cell character that upon proliferation and differentiation produce advanced metastatic disease and a poor outcome.

References:

Cheung, K.J., E. Gabrielson, Z. Werb & A. J. Ewald (2013). Collective invasion in breast cancer requires a conserved basal epithelial program. Cell. 155: 1639-1651.

Plaks, V., N. Kong & Z. Werb (2015). The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16: 225-238.

Lawson, D. A., N. Bhakta, K. Kessenbrock, K. Prummel, Y. Yu, K. Takai, A. Zhou, H. Eyob, S. Balakrishnan, C.-Y. Wang, P. Yaswen, A. Goga & Z. Werb (2015). Single-cell analysis reveals a stem cell program in early human metastatic breast cancer cells. Nature. In press.

Citation Format: Devon Lawson, Kai Kessenbrock, Zena Werb. A stem cell program in early human metastatic breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA24.
Abstract A30: AKT activation as a mechanism of escape from TGFβ-mediated lethal EMT
Authors: Huang Yun-Han , David Charles , Massague Joan
Published: May 2016

Frequent inactivation of transforming growth factor β (TGFβ) pathway core components in pancreatic ductal adenocarcinoma (PDA), especially the transcription factor SMAD4, suggests that TGFβ signaling is tumor suppressive in the pancreas. Yet, 50% of PDA retains an intact core TGFβ pathway, suggesting that there are mechanisms by which these tumors escape TGFβ-mediated tumor suppression. In unpublished work, we have delineated a mechanism for TGFβ-mediated tumor suppression via a lethal epithelial-mesenchymal transition (EMT). Based on clinical and in vitro evidence that AKT activation may suppress the lethal EMT response to TGFβ, we are investigating the role of AKT signaling in directly interfering with TGFβ-mediated tumor suppression. We have taken two major approaches: (1) to test the concept that AKT inhibition may reactivate TGFβ-mediated tumor suppression, we are chemically inhibiting AKT in PDA mouse models competent and deficient in TGFβ signaling, and (2) to understand the mechanism of AKT-TGFβ crosstalk in PDA progression, we are performing RNAseq-based gene expression profiling of SMAD4-restored PDA cell lines. We have found that in vitro, AKT signaling determines whether TGFβ induces apoptosis in SMAD4-restored PDA cell lines, and by gene expression analysis, we have identified a group of genes that are differentially regulated by TGFβ in the presence and absence of AKT signaling. Furthermore, we have characterized FOXO immunohistochemical staining as a reliable marker for AKT inhibition status and developed an in vivo system in which we are testing whether AKT inhibition may be a means to reactivate TGFβ-mediated tumor suppression in PDA. Our studies indicate that AKT signaling may alter the outcome of TGFβ-mediated tumor suppression in the pancreas, and our ongoing work is aimed at dissecting the AKT-modulated transcriptional mechanisms that determine the outcome of TGFβ signaling and the consequences of this crosstalk in tumor progression.

Citation Format: Yun-Han Huang, Charles David, Joan Massague. AKT activation as a mechanism of escape from TGFβ-mediated lethal EMT. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A30.
Abstract A36: Notch signaling promotes tumor metastasis in the Pten null mouse model for prostate cancer
Authors: Kwon Oh-Joon , Zhang Li , Jianghua Wang , Creighton Chad , Ittmann Michael , Xin Li
Published: May 2016

The role of Notch signaling in prostate cancer remains inconclusive. We show that a higher Notch signature score is significantly correlated with higher disease grade, metastatic potential and higher probability of lethal outcome in two published human prostate cancer datasets. We employ genetic approaches to investigate the role of Notch signaling in initiation and progression of prostate cancer in a Pten null mouse model. Notch signaling is dispensable for disease initiation and progression in this model. Elevated Notch activity in the Pten null model promotes both epithelial proliferation and apoptosis, which collectively results in a reduction of primary tumor burdens. Despite reduced primary tumor burdens, Notch activation drives epithelial-mesenchymal-transition and promotes distal tumor metastases at full penetrance. Our study reveals distinct impacts of Notch signaling on cancer cell proliferation, survival and metastasis in the context of Pten loss, and highlights a multifaceted and pleiotropic role of Notch in regulating the different aspects of prostate cancer cell biology.

Citation Format: Oh-Joon Kwon, Li Zhang, Wang Jianghua, Chad Creighton, Michael Ittmann, Li Xin. Notch signaling promotes tumor metastasis in the Pten null mouse model for prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A36.