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  • American Association for Cancer Research (AACR)  (6)
  • 1
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    Online Resource
    Abstract 2996: Creating PDXs from continental African breast tumors: addressing racial inequity through science
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2996-2996
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2996-2996
    Abstract: To design interventions to reduce the burden of breast cancer (BC) in women with African ancestry, there is the need to understand the factors - heritable or non-heritable, modifiable or non-modifiable - that are associated with the disease. Patients and tumors from black women have been underrepresented in clinical research which are the main route to identifying new and improved treatments. Triple negative breast cancer (TNBC) is a clinically aggressive form of BC with propensity to metastasize and is enriched in patients with hereditary predisposition to BC. TNBC is most prevalent among black women despite lacking strong links with the known BC. This phenotype prevalence contributes to disparities in BC outcomes between blacks and other populations. There is an urgent need to represent black tumors in clinical research. Here we describe the process we used to transport fresh breast tumors from Ghana, west Africa to the USA to develop PDXs. Considering the shared ancestry between west Africans and diasporan African American, the results of this work will benefit both populations. Through an international collaboration between investigators at University of Michigan (UM) and Komfo Anokye Teaching Hospital (KATH) in Ghana, regular team site visits were initiated to generate surgical specimens for transport to the United States of America (USA). These specimens were used to create in vivo models. With informed consent, excess patient tumor tissue was taken from the operating room, at KATH. The tumors were cut into small pieces, and slow- frozen to -80°C in 10% DMSO/90%FBS. The samples were then transported overnight on dry ice in a commercial flight to UM. At UM, the tumor pieces were rapidly thawed and rinsed off with HBSS or PBS. The tumor sample was cut into smaller fragments (approximately 1-2 mm in diameter), mixed with matrigel (BD), and 25 μl of matrigel per injection site was injected into the mammary fat pad of female NOD/scid/IL2Rgnull (NSG) mice with an 18-gauge needle. From 2012 to 2017, we obtained fresh tumor samples from 49 Ghanaian patients. Of these, 23 (47%) were TNBC and 26 (53%) were other subtypes. Of the 23 TNBC samples, we implanted 18 into NSG mice and developed PDXs from 12. This gave us a success rate of 67%. We have fully characterized these tumors and their corresponding primary tumors. Our results demonstrate a maintenance of the histology and marker expression in the corresponding PDXs. Additionally, we obtained samples and developed PDXs from 17 Caucasian Americans, 13 African Americans, and 2 Asian patients from UM. 20 samples were TNBCs and 13 were non-TNBC. 18 were implanted in mice (12 TNBC, 4 ER+, and 2 Her2+). Of these, 11 developed into PDXs (9 TNBC, 2 ER+). Transporting African tumors to the USA is expensive, challenging, and limits large scale studies. These challenges can be overcome by enhancing African based research resources in order to conduct research in Africa. Citation Format: Evelyn M. Jiagge, Tahra K. Suhan, Jessica M. Bensenhaver, Michele Dziubinski, Joseph K. Oppong, Francis Aitpillah, Awuah Baffour, John D. Carpten, Lisa A. Newman, Sofia D. Merajver, Max S. Wicha. Creating PDXs from continental African breast tumors: addressing racial inequity through science [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2996.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2996
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 11 ( 2022-11-02), p. 2530-2551
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 11 ( 2022-11-02), p. 2530-2551
    Abstract: Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. Significance: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race–group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-22-0138
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
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    Abstract 3371: Aldh expressing stem cells mediate tumor initiation and metastasis in triple negative breast cancers across different ethnicities
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3371-3371
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3371-3371
    Abstract: TNBC is the only subtype of breast cancer for which there are no approved targeted therapies. In the US, its incidence is highest in women with African ancestry (AA); in western sub-Saharan Africa, single-institution studies show that TNBC constitutes 40- 80% of all breast cancers. Given the Caucasian/AA survival disparity in breast cancer, there is an urgent need to find actionable targets in TNBC of all ethnicities, but especially in TNBC in AA, which are suspected to be more aggressive. Breast cancer stem cells, the small population of cells that have been shown to mediate breast tumor initiation, metastasis, and resistance to conventional therapy have also been reported to mediate the heterogeneity of TNBC and are especially abundant in TNBC in AA women. Here, we sought to better understand the biology of TNBC by finding genes and pathways that are differentially expressed in the stem cell population of patient derived xenografts (PDX) from TNBC from Ghanaian (G), AA and Caucasian (C) women and the effect of these differentially expressed genes on the stem cell phenotype in these primary tumors. We isolated the ALDH+ and the CD44+/CD24- stem cell populations from the bulk cells from 15 PDXs using flow cytometry. We performed RNA sequencing (Illumina HiSeq platform) on the isolated populations and bulk cells (45). Comprehensive bioinformatics analyses led to the identificationof highly significantly differentially expressed genes and pathways between the cell populations. By principal component analysis, the tumors were very heterogeneous. However, the ALDH+ cells separated out from the CD44+/CD24- and the bulk cells. We identified 14 genes that were simultaneously differentially expressed between the ALDH+ vs the CD44+/CD24- as well as ALDH+ VS bulk (p-value & lt;0.001, FDR & lt; 0.05). The 3 most significant genes were MMP2 and PCDH7, both known to be involved in breast cancer metastasis and CPXM1, a carboxylase. Inhibiting MMP2 expression in the PDX cells grown in suspension resulted in significant reduction in the ALDH+ cell population. Also, the ALDH+ and not the CD44+/CD24- cells formed spheres in serum free media. The WNT, MAPK and TGF-beta pathways known to mediate metastasis were all significantly up-regulated in the ALDH+ population with down regulation of biosynthetic pathways which were up-regulated in the CD44+/CD24- population. Further studies are ongoing on pathway modulation in ALDH1+ cells based on these findings. Our data demonstrate that the ALDH+ stem cell population is enriched for tumor initiating cells in aggressive TNBCs across different ethnicities. These cells may play a role in mediating the aggressive behavior of TNBC’s found in African women. Citation Format: Evelyn M. Jiagge, Shukmei Wong, Rabia Gilani, Sean Mcdermott, Lisa Newman, Jessica Bensenhaver, Max Wicha, John Carpten, Sofia Merajver. Aldh expressing stem cells mediate tumor initiation and metastasis in triple negative breast cancers across different ethnicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2017-3371
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3371
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Abstract PO-189: Precision medicine for African breast cancer: Bringing African researchers together to study African breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 12_Supplement ( 2020-12-01), p. PO-189-PO-189
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 12_Supplement ( 2020-12-01), p. PO-189-PO-189
    Abstract: Introduction In sub-Saharan Africa, breast cancer (BC) is the leading cancer in women and the second cause of cancer mortality. In order to reduce the burden of BC in women with African ancestry there is a need for a structured, coordinated effort to address gaps in our understanding of the factors associated with the disease that influence tumor initiation, progression, and outcomes. To address this need ‘Precision Medicine for African Breast Cancer (PMABC)’ a comprehensive partnership housed at the Henry Ford Cancer Institute was created with the aim of bringing together African researchers to study African BC. We are currently composed of nine leading institutions spanning West and East Africa and two institutions in the United States. Objectives The broad aim of PMABC is to bring together researchers and institutions across sub-Saharan Africa to partner with foreign institutions and funding agencies to study and identify new and improved methods of screening, diagnosing, and treating BC in Africans to improve the overall outcome. Among the aims of PMABC are: • Registry: Create a national BC registry building on data from participating institutions which comprise at least 80% of all BC cases seen in the respective country • Standardization of pathology protocol and reporting: harmonize the pathology reporting scheme and ensure its conformity to international standards Standardization of treatment protocols: Study and compare treatment protocols with international standards and make recommendations • Biorepository: Create a national repository of patient samples to be used in genetic and biological studies • Study African tumor biology: Build the capacity to be able to study African tumors locally and participate in clinical trials • Patient follow up and survival studies: study and obtain data on patient outcomes Achievements We currently have ethical approval and have begun work in nine institutions across West and East Africa. • Creation of a national database in Ghana that currently consists of over 7000 patients. The data is being analyzed to determine risk factors and the distribution of BC by subtypes • We are setting up two research labs in Ghana to train local researchers for basic and translational research • We have a biorepository of over 2000 patient samples that is available for collaborative studies • We have developed tumor models from continental African breast tumors • Building partnership with international organizations, pharmaceutical companies, and funding agencies to study African BC Conclusion PMABC serves as an umbrella institution to coordinate the work between these researchers and to provide resources for the institutions to provide a high level of BC research and treatment. We are aiming to partner with countries across Africa to translate the model created by PMABC in order fulfill the need for further BC research and standardization of data collection and treatment. PMABC is made possible because of the dedication and passion of our collaborating researchers. Citation Format: Sabrina I. Fossi, Sylvester Antwi, Kwabena Agbedinu, Kafui Akakpo, Samuel Mensah, Nelson Affram, Mohammed Sheriff, Foster Amponsah, Jacqueline Asibey, Osei Collins, Alex Mremi, Livingstone Aduse-Poku, Kurt Fernando, Haythem Ali, Eleanor Walker, Jessica Bensenhaver, Evelyn M. Jiagge. Precision medicine for African breast cancer: Bringing African researchers together to study African breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-189.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP20-PO-189
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract 1639: Androgen receptor and ALDH1 expression among internationally diverse patient populations
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1639-1639
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1639-1639
    Abstract: Background: Population-based incidence rates of breast cancers that are negative for the estrogen receptor (ER), progesterone receptor (PR), HER2/neu triple-negative breast cancer (TNBC) are higher among African American (AA) compared to White American (WA) women, and several studies suggest that TNBC prevalence is increased among selected populations of African patients. The colonial-era transatlantic slave trade resulted in shared ancestry between contemporary AA and Gh populations. The extent to which associations between TNBC are related to East African versus West African ancestry, and whether these associations extend to expression of additional hormone receptors such as androgen receptor (AR) and stem cell markers such as ALDH1, is uncertain, but this research may explain breast cancer disparities between domestic communities within the United States as well as between international population subsets. Methods: We utilized immunohistochemistry to evaluate ER, PR, HER2/neu, AR and ALDH1 expression among White American (n=153), African American (n=76), Ethiopian (Eth)/East African (n=90), and Ghanaian (Gh)/West African (n=286) breast cancers through an IRB-approved international research program. Results: Mean age at breast cancer diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. Frequency of TNBC was significantly higher for the AA and Gh patients (41% and 54%, respectively) compared to the WA and Eth patients (23% and 15%, respectively; p & lt;0.001). These associations were unchanged when limited to patients age 50 years and younger (47% and 49% for AA and Gh, respectively, versus 18% and 16% for WA and Eth, respectively; p & lt;0.001). Frequency of ALDH1 positivity was also higher for the AA and Gh tumors (32% and 36%, respectively) compared to the WA and Eth tumors (23% and 17%, respectively; p=0.007). Significant differences were also observed for distribution of AR positivity, which was 71%, 55%, 42%, and 50% for the WA, AA, Gh, and Eth cases, respectively (p=0.008). Frequency of ALDH1 expression was numerically higher in the AA, Gh, and Eth TNBC cases compared to the WA TNBC cases, but this was not statistically significant (33%, 41%, and 31%, respectively, versus 18%; p=0.47). Conclusions: Extent of African ancestry appears to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1. Citation Format: Evelyn M. Jiagge, Aisha Jibri, Jessica Bensenhaver, Max Wicha, Baffour Awuah, Sofia Merajver, Lisa Newman. Androgen receptor and ALDH1 expression among internationally diverse patient populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1639.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-1639
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract PL03-03: Differences in breast cancer stem cell signaling and metabolic integration associated with African versus European ancestry
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 11_Supplement ( 2014-11-01), p. PL03-03-PL03-03
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 11_Supplement ( 2014-11-01), p. PL03-03-PL03-03
    Abstract: In the US where extensive studies have been conducted, African-American(AA) women have poorer survival from breast cancer (BC) even after adjusting for stage, age, treatment and co-morbid conditions. Since survival in BC is mainly dependent on the appearance and robustness of metastasis, we have hypothesized that BC occurring in women with African ancestry have a greater metastatic potential. With the growing evidence that BC tumor initiation, metastases and recurrence is driven by stem-like cancer cells, we further hypothesize that BC in women of African descent has aggressive phenotypic characteristics that result from the integration of signaling alterations and metabolic adaptations in their cancer stem cells. Rodent xenograft models are powerful tools for studying tumor biology and treatment response to novel agents, but they are challenging to develop in the laboratory. Here we describe the first-ever creation of a library of xenografts from a series of patients affected with triple negative breast cancer (TNBC) from sub-Saharan Africa, based upon a unique international collaboration; we also report on studies that are being conducted on the xenografts to understand the stem cell biology of aggressive African breast cancers. Methods: Our research team explored several different strategies for obtaining fresh tumor specimens from Ghanaian patients with aggressive TNBC tumors, undergoing surgery in Kumasi, Ghana, and rapidly transporting these tissues for implantation into immunocompromised mice in the United States. Xenograft tumors were also developed from AA and Caucasian American (CA) patients undergoing surgery in the United States. The whole genome expression patterns of the bulk tumor as well as the stem cell compartments were compared for AA, Ghanaian and CA TNBC. Single cells from the tumors were grown in suspension and in attachment plates. Results: Successful xenografts were created by harvesting fresh tissue from patients undergoing surgery in Ghana, slow freezing tumor pieces at -80o C and transporting it on dry ice by air to the United States within 24-36 hours to implant into nod scid gamma mice. Currently we have successful growth, as follows: 12 tumors from 4 patients growing in 10 mice. We have successful growth of tumorspheres and cell lines from single cells separated from the xenografts, as additional resources for biological studies of signaling and metastases. In a preliminary study, we have performed a gene array expression study of AA and White American triple negative and estrogen positive cell lines that show significantly different gene expression patterns, with the cell lines of high African ancestry segregating from Caucasian cell lines . Conclusions: The study of aggressive breast cancers in African populations is feasible through the creation of xenografts from fresh tumor tissue harvested from the treating facilities and transported to laboratories in the United States. International collaborations are critical for this process and should thus be encouraged, to create the appropriate resources worldwide to improve our understanding of aggressive BC subtypes.. Moreover, we are finding common expression patterns in TNBC of African extraction. This will help advance our understanding of the survival disparities. To this end, we will be able to test the observed differences in the new tumorspheres and cell lines developed directly from patients. Citation Format: Evelyn M. Jiagge, Jessica Bensenhaver, Sean McDermott, Awuah Baffour, Max Wicha, Lisa A. Newman, Sofia Merajver. Differences in breast cancer stem cell signaling and metabolic integration associated with African versus European ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PL03-03. doi:10.1158/1538-7755.DISP13-PL03-03
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP13-PL03-03
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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