Relationships between parity, breastfeeding and ER- breast cancer in African American women: Elucidating the biologic underpinnings at the molecular and cellular level.

非裔美国女性的产次、母乳喂养和 ER-乳腺癌之间的关系:阐明分子和细胞水平的生物学基础。

基本信息

项目摘要

ABSTRACT: African-American (AA) women are more likely than other US groups to be diagnosed with estrogen receptor negative (ER-) breast cancer, with poorer prognosis and higher mortality. Understanding the biological mechanisms underlying ER- breast cancer in AA women and developing effective preventive strategies represents a critical unmet need with major public health implications. We and others have shown that risk of ER- breast cancer is increased among AA women who are parous and do not breastfeed; factors that are more common among AA women, and may help to explain their higher incidence of ER- tumors. We hypothesize that specific reproductive exposures result in epigenetic silencing of pro-luminal differentiation genes via DNA methylation, leading to an expansion of aberrant, maturation-arrested luminal progenitor cells, which can give rise to ER- cancers. Our previous data showed distinct differences in tumor DNA methylation according to ER status. One strong candidate gene derived from these data is FOXA1, which promotes luminal cell differentiation by positively regulating a luminal gene expression signature in progenitor cells and repressing the basal cell phenotype. This gene was hyper-methylated in ER- versus ER+ tumors from AA women, particularly in those who were parous and did not breastfeed. Consistent with inhibitory effects of methylation on gene expression, FOXA1 protein levels were lower in ER- versus ER+ breast tumors, and lower in ER- tumors from parous vs. nulliparous women. Supporting this hypothesis, we recently showed that heterozygous deletion of Foxa1 in the mouse mammary gland results in a dramatic skewing of epithelial cell populations toward luminal progenitors. Building on these preliminary results, we propose a comprehensive genome-wide DNA methylation analysis of tumor samples from 1,621 AA women with breast cancer from the Black Women's Health Study) and the Women's Circle of Health Study using the IIllumina EPIC 850K array. Combining these profiles with existing 450K data from 383 AA cases after methylation imputation, we will examine FOXA1 and differentially methylated loci (DMLs) that distinguish ER subgroups. With epidemiologic data from these 2,004 AA cases, we will assess associations between reproductive risk factors and methylation of FOXA1 and top DMLs, using weighted gene correlation network analysis and structural equation modeling to evaluate complex relationships. We will evaluate the same relationships between parity, breastfeeding and methylation in normal breast tissue donated by healthy AA volunteers to the Komen Tissue Bank. Using mouse models, we will experimentally investigate if parity and breastfeeding influence the methylation level of Foxa1 and other pro-luminal candidate genes, as well as relative proportions of distinct mammary gland epithelial cell populations. This transdisciplinary, multi-pronged approach will enable us to understand the etiology of aggressive breast cancer in AA women, facilitate the development of novel markers for those at highest risk, and uncover promising molecular targets for precision prevention approaches.
摘要:非裔美国 (AA) 女性比其他美国群体更有可能被诊断出患有 雌激素受体阴性(ER-)乳腺癌的预后较差,死亡率较高。了解 AA 女性 ER-乳腺癌的生物学机制和开发有效的预防措施 战略代表了一个未满足的关键需求,对公共卫生产生重大影响。我们和其他人已经表明 已生育且不进行母乳喂养的 AA 女性患 ER-乳腺癌的风险增加;因素 这在 AA 女性中更为常见,可能有助于解释她们 ER 肿瘤发病率较高的原因。我们 假设特定的生殖暴露导致前腔分化的表观遗传沉默 基因通过DNA甲基化,导致异常的、成熟停滞的管腔祖细胞的扩增, 这可能会导致 ER- 癌症。我们之前的数据显示肿瘤 DNA 甲基化存在明显差异 根据 ER 状态。从这些数据中得出的一个强有力的候选基因是 FOXA1,它促进管腔 通过正向调节祖细胞中的管腔基因表达特征来实现细胞分化, 抑制基底细胞表型。该基因在 AA 的 ER- 与 ER+ 肿瘤中高度甲基化 女性,尤其是那些已生育且未进行母乳喂养的女性。与抑制作用一致 甲基化对基因表达的影响,ER- 与 ER+ 乳腺肿瘤中的 FOXA1 蛋白水平较低,并且 经产妇与未产妇的 ER-肿瘤。为了支持这一假设,我们最近表明 小鼠乳腺中 Foxa1 的杂合缺失导致上皮细胞的显着倾斜 群体走向管腔祖细胞。基于这些初步结果,我们提出了一项全面的 对 1,621 名患有乳腺癌的 AA 女性的肿瘤样本进行全基因组 DNA 甲基化分析 黑人女性健康研究)和女性健康圈研究使用 IIllumina EPIC 850K 阵列。 将这些概况与甲基化插补后来自 383 个 AA 病例的现有 450K 数据相结合,我们将 检查 FOXA1 和区分 ER 亚组的差异甲基化位点 (DML)。具有流行病学 根据这 2,004 个 AA 病例的数据,我们将评估生殖风险因素与 FOXA1 和顶级 DML 的甲基化,使用加权基因相关网络分析和结构方程 建模来评估复杂的关系。我们将评估奇偶性之间的相同关系, 健康 AA 志愿者向 Komen 组织捐赠的正常乳腺组织中的母乳喂养和甲基化 银行。使用小鼠模型,我们将通过实验研究胎次和母乳喂养是否会影响 Foxa1 和其他前腔候选基因的甲基化水平,以及不同的相对比例 乳腺上皮细胞群。这种跨学科、多管齐下的方法将使我们能够 了解 AA 女性侵袭性乳腺癌的病因,促进新标志物的开发 针对那些风险最高的人,并发现有希望的分子目标,以实现精准的预防方法。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Proceedings of the fifth international Molecular Pathological Epidemiology (MPE) meeting.
  • DOI:
    10.1007/s10552-022-01594-7
  • 发表时间:
    2022-08
  • 期刊:
  • 影响因子:
    2.3
  • 作者:
    Yao, Song;Campbell, Peter T.;Ugai, Tomotaka;Gierach, Gretchen;Abubakar, Mustapha;Adalsteinsson, Viktor;Almeida, Jonas;Brennan, Paul;Chanock, Stephen;Golub, Todd;Hanash, Samir;Harris, Curtis;Hathaway, Cassandra A.;Kelsey, Karl;Landi, Maria Teresa;Mahmood, Faisal;Newton, Christina;Quackenbush, John;Rodig, Scott;Schultz, Nikolaus;Tearney, Guillermo;Tworoger, Shelley S.;Wang, Molin;Zhang, Xuehong;Garcia-Closas, Montserrat;Rebbeck, Timothy R.;Ambrosone, Christine B.;Ogino, Shuji
  • 通讯作者:
    Ogino, Shuji
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Christine B. Ambrosone其他文献

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification
对超过 40 万名女性的分析为 BRCA1 和 BRCA2 变异分类提供了病例对照证据
  • DOI:
    10.1038/s41467-025-59979-6
  • 发表时间:
    2025-05-25
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Maria Zanti;Denise G. O’Mahony;Michael T. Parsons;Leila Dorling;Joe Dennis;Nicholas J. Boddicker;Wenan Chen;Chunling Hu;Marc Naven;Kristia Yiangou;Thomas U. Ahearn;Christine B. Ambrosone;Irene L. Andrulis;Antonis C. Antoniou;Paul L. Auer;Caroline Baynes;Clara Bodelon;Natalia V. Bogdanova;Stig E. Bojesen;Manjeet K. Bolla;Kristen D. Brantley;Nicola J. Camp;Archie Campbell;Jose E. Castelao;Melissa H. Cessna;Jenny Chang-Claude;Fei Chen;Georgia Chenevix-Trench;Don M. Conroy;Kamila Czene;Arcangela De Nicolo;Susan M. Domchek;Thilo Dörk;Alison M. Dunning;A. Heather Eliassen;D. Gareth Evans;Peter A. Fasching;Jonine D. Figueroa;Henrik Flyger;Manuela Gago-Dominguez;Montserrat García-Closas;Gord Glendon;Anna González-Neira;Felix Grassmann;Andreas Hadjisavvas;Christopher A. Haiman;Ute Hamann;Steven N. Hart;Mikael B. A. Hartman;Weang-Kee Ho;James M. Hodge;Reiner Hoppe;Sacha J. Howell;Anna Jakubowska;Elza K. Khusnutdinova;Yon-Dschun Ko;Peter Kraft;Vessela N. Kristensen;James V. Lacey;Jingmei Li;Geok Hoon Lim;Sara Lindström;Artitaya Lophatananon;Craig Luccarini;Arto Mannermaa;Maria Elena Martinez;Dimitrios Mavroudis;Roger L. Milne;Kenneth Muir;Katherine L. Nathanson;Rocio Nuñez-Torres;Nadia Obi;Janet E. Olson;Julie R. Palmer;Mihalis I. Panayiotidis;Alpa V. Patel;Paul D. P. Pharoah;Eric C. Polley;Muhammad U. Rashid;Kathryn J. Ruddy;Emmanouil Saloustros;Elinor J. Sawyer;Marjanka K. Schmidt;Melissa C. Southey;Veronique Kiak-Mien Tan;Soo Hwang Teo;Lauren R. Teras;Diana Torres;Amy Trentham-Dietz;Thérèse Truong;Celine M. Vachon;Qin Wang;Jeffrey N. Weitzel;Siddhartha Yadav;Song Yao;Gary R. Zirpoli;Melissa S. Cline;Peter Devilee;Sean V. Tavtigian;David E. Goldgar;Fergus J. Couch;Douglas F. Easton;Amanda B. Spurdle;Kyriaki Michailidou
  • 通讯作者:
    Kyriaki Michailidou
Association between TP53 and p21 genetic polymorphisms and acute side effects of radiotherapy in breast cancer patients
  • DOI:
    10.1007/s10549-005-9119-2
  • 发表时间:
    2005-12-06
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Xiang-Lin Tan;Odilia Popanda;Christine B. Ambrosone;Silke Kropp;Irmgard Helmbold;Dietrich von Fournier;Wulf Haase;Marie Luise Sautter-Bihl;Frederik Wenz;Peter Schmezer;Jenny Chang-Claude
  • 通讯作者:
    Jenny Chang-Claude
Erratum to: DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study
  • DOI:
    10.1007/s10549-013-2660-5
  • 发表时间:
    2013-08-01
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Meng Hua Tao;Peter G. Shields;Jing Nie;Amy Millen;Christine B. Ambrosone;Stephen B. Edge;Shiva S. Krishnan;Catalin Marian;Bin Xie;Janet Winston;Dominica Vito;Maurizio Trevisan;Jo L. Freudenheim
  • 通讯作者:
    Jo L. Freudenheim
Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions
通过对 192 个风险区域的多祖先精细定位分析来完善乳腺癌的遗传风险和生物学
  • DOI:
    10.1038/s41588-024-02031-y
  • 发表时间:
    2025-01-03
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Guochong Jia;Zhishan Chen;Jie Ping;Qiuyin Cai;Ran Tao;Chao Li;Joshua A. Bauer;Yuhan Xie;Stefan Ambs;Mollie E. Barnard;Yu Chen;Ji-Yeob Choi;Yu-Tang Gao;Montserrat Garcia-Closas;Jian Gu;Jennifer J. Hu;Motoki Iwasaki;Esther M. John;Sun-Seog Kweon;Christopher I. Li;Koichi Matsuda;Keitaro Matsuo;Katherine L. Nathanson;Barbara Nemesure;Olufunmilayo I. Olopade;Tuya Pal;Sue K. Park;Boyoung Park;Michael F. Press;Maureen Sanderson;Dale P. Sandler;Chen-Yang Shen;Melissa A. Troester;Song Yao;Ying Zheng;Thomas Ahearn;Abenaa M. Brewster;Adeyinka Falusi;Anselm J. M. Hennis;Hidemi Ito;Michiaki Kubo;Eun-Sook Lee;Timothy Makumbi;Paul Ndom;Dong-Young Noh;Katie M. O’Brien;Oladosu Ojengbede;Andrew F. Olshan;Min-Ho Park;Sonya Reid;Taiki Yamaji;Gary Zirpoli;Ebonee N. Butler;Maosheng Huang;Siew-Kee Low;John Obafunwa;Clarice R. Weinberg;Haoyu Zhang;Hongyu Zhao;Michelle L. Cote;Christine B. Ambrosone;Dezheng Huo;Bingshan Li;Daehee Kang;Julie R. Palmer;Xiao-Ou Shu;Christopher A. Haiman;Xingyi Guo;Jirong Long;Wei Zheng
  • 通讯作者:
    Wei Zheng
Proceedings of the fourth international molecular pathological epidemiology (MPE) meeting
  • DOI:
    10.1007/s10552-019-01177-z
  • 发表时间:
    2019-05-08
  • 期刊:
  • 影响因子:
    2.100
  • 作者:
    Peter T. Campbell;Christine B. Ambrosone;Reiko Nishihara;Hugo J. W. L. Aerts;Melissa Bondy;Nilanjan Chatterjee;Montserrat Garcia-Closas;Marios Giannakis;Jeffrey A. Golden;Yujing J. Heng;N. Sertac Kip;Jill Koshiol;X. Shirley Liu;Camila M. Lopes-Ramos;Lorelei A. Mucci;Jonathan A. Nowak;Amanda I. Phipps;John Quackenbush;Robert E. Schoen;Lynette M. Sholl;Rulla M. Tamimi;Molin Wang;Matty P. Weijenberg;Catherine J. Wu;Kana Wu;Song Yao;Kun-Hsing Yu;Xuehong Zhang;Timothy R. Rebbeck;Shuji Ogino
  • 通讯作者:
    Shuji Ogino

Christine B. Ambrosone的其他文献

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{{ truncateString('Christine B. Ambrosone', 18)}}的其他基金

Relationships between parity, breastfeeding and ER- breast cancer in African American women: Elucidating the biologic underpinnings at the molecular and cellular level.
非裔美国女性的产次、母乳喂养和 ER-乳腺癌之间的关系:阐明分子和细胞水平的生物学基础。
  • 批准号:
    10303040
  • 财政年份:
    2018
  • 资助金额:
    $ 59.22万
  • 项目类别:
Relationships between parity, breastfeeding and ER- breast cancer in African American women: Elucidating the biologic underpinnings at the molecular and cellular level.
非裔美国女性的产次、母乳喂养和 ER-乳腺癌之间的关系:阐明分子和细胞水平的生物学基础。
  • 批准号:
    10057367
  • 财政年份:
    2018
  • 资助金额:
    $ 59.22万
  • 项目类别:
Infrastructure for Pathways, a Prospective Study of Breast Cancer Survivorship
通路基础设施,乳腺癌存活率的前瞻性研究
  • 批准号:
    10622554
  • 财政年份:
    2016
  • 资助金额:
    $ 59.22万
  • 项目类别:
Infrastructure for Pathways, a Prospective Study of Breast Cancer Survivorship
通路基础设施,乳腺癌存活率的前瞻性研究
  • 批准号:
    10439575
  • 财政年份:
    2016
  • 资助金额:
    $ 59.22万
  • 项目类别:
Infrastructure for Pathways, a Prospective Study of Breast Cancer Survivorship
通路基础设施,乳腺癌存活率的前瞻性研究
  • 批准号:
    9044480
  • 财政年份:
    2016
  • 资助金额:
    $ 59.22万
  • 项目类别:
Infrastructure for Pathways, a Prospective Study of Breast Cancer Survivorship
通路基础设施,乳腺癌存活率的前瞻性研究
  • 批准号:
    9980180
  • 财政年份:
    2016
  • 资助金额:
    $ 59.22万
  • 项目类别:
Infrastructure for Pathways, a Prospective Study of Breast Cancer Survivorship
通路基础设施,乳腺癌存活率的前瞻性研究
  • 批准号:
    10081095
  • 财政年份:
    2016
  • 资助金额:
    $ 59.22万
  • 项目类别:
Invasive breast cancer with and without DCIS: Race, risk factors and outcomes
伴或不伴 DCIS 的浸润性乳腺癌:种族、危险因素和结果
  • 批准号:
    8634076
  • 财政年份:
    2013
  • 资助金额:
    $ 59.22万
  • 项目类别:
Invasive breast cancer with and without DCIS: Race, risk factors and outcomes
伴或不伴 DCIS 的浸润性乳腺癌:种族、危险因素和结果
  • 批准号:
    8512328
  • 财政年份:
    2013
  • 资助金额:
    $ 59.22万
  • 项目类别:
Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
非裔美国女性乳腺癌亚型的流行病学:一个联盟
  • 批准号:
    8523798
  • 财政年份:
    2011
  • 资助金额:
    $ 59.22万
  • 项目类别:

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