Addressing cancer disparity through defining the molecular link between breast feeding and triple negative breast cancer
通过定义母乳喂养与三阴性乳腺癌之间的分子联系来解决癌症差异
基本信息
- 批准号:10372950
- 负责人:
- 金额:$ 43.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-03-06 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAfrican AmericanBRCA1 geneBreastBreast Cancer Risk FactorBreast Epithelial CellsBreast FeedingCancer Death RatesCaucasiansCell CompartmentationCell ProliferationCellsChIP-seqChronicCollagenDepositionDevelopmentDiagnosisEpidemiologistEpidemiologyEpithelialEstrogen AntagonistsEstrogen receptor negativeEstrogensFVB/N MouseFaceGene ChipsGene Expression ProfilingGenesGlandGlobal ChangeGrantHistologicHumanHyperplasiaIn VitroIncidenceInflammationInflammatoryInflammatory ResponseKnockout MiceLactationLesionLinkMammary Gland ParenchymaMammary NeoplasmsMammary glandMediatingMessenger RNAMetaplasiaMethodsModelingMolecularMothersMouse Mammary Tumor VirusMusMutateOncogenicOutcomePathway interactionsPatientsPhenotypePopulationPopulation StudyPostpartum PeriodPre-Clinical ModelPregnancyPremenopausePrevalencePreventionPrevention strategyProcessProteinsRiskRisk FactorsRoleSamplingSignal TransductionStudy modelsTamoxifenTherapeuticTimeTissue BanksTissuesTranslatingWeaningWomanWorkbaseblack womencancer health disparitychemical carcinogencohortconditional knockoutdimethylbenzanthracenedisparity reductionepidemiology studyepithelial stem cellhigh riskhuman modelinflammatory markerinnovationmacrophagemalignant breast neoplasmmammarymammary epitheliummortalitymouse modelmutation carriernovelparityparouspremalignantpreventive interventionprogenitorprotective effectracial differencerecruitstem cellstranscription factortranslational impacttriple-negative invasive breast carcinomatumortumor initiationtumor progression
项目摘要
PROJECT SUMMARY
The long-term objective of this proposal is to reduce the risk of developing aggressive triple negative breast
cancer (TNBC), especially for African-American women (AAW), by discovering how prolonged breastfeeding
protects the breast from this risk. AAW have lower breastfeeding rates that likely contribute to the higher
incidence of TNBC and higher mortality. Therefore, our work will specifically address this disparity in breast
cancer outcomes faced by AAW. We developed unique mouse models for studying gradually involuting (GI-
prolonged breastfeeding) vs abruptly involuting (AI-short breastfeeding) mammary glands. We have shown
dramatic shifts in cellular composition of the mammary epithelial cell compartment and global changes in
inflammatory markers and importantly have observed precancerous hyperplastic lesions within 120 days
postpartum in the AI glands. These precancerous glands highly expressed the transcription factor Elf5, a key
gene expressed by luminal progenitor cells, the cell-of-origin for TNBC. Based on these studies, we hypothesize
that lack of breastfeeding not only alters the cellular composition and increases inflammation but leads to a
higher risk of developing TNBC through Elf5 mediated aberrant differentiation: In this proposal, we will use
innovative approaches including novel mouse models and patient samples to delineate the link between
breastfeeding and TNBC. Aim 1A: Delineate the protective effects of GI vs. AI in mouse models of human breast
cancer. 1B. determine if blocking estrogen signaling will abrogate the hyperplastic changes induced by AI. We
will use MMTV-Cre;Brca1fl/fl;p53fl/fl mice and a chemical-carcinogen induced model to assess if AI accelerates
tumor incidence and progression of TNBC. We will treat AI mice with tamoxifen to assess if progression to
hyperplasia is mitigated. Aim 2: Elucidate the role of Elf5 and alterations in the microenvironment (ME) that led
to the precancerous changes seen in the AI mammary glands. We will use mammary-specific Elf5 conditional
knock-out mouse models and in vitro methods for this aim. Gene expression and CHIP-Seq will be utilized to
identify the downstream effectors of Elf5. We will determine the differences in the ME between AI versus GI
glands, especially the recruitment of different types of macrophages. Aim 3: Validate the histological and
molecular changes observed in mice using human mammary tissue obtained from parous women who breastfed
0-3 (AI) vs. > 6 months (GI). We will obtain FFPE breast tissue from the Susan G. Komen for the Cure® Tissue
Bank to study the differences in collagen deposition and other inflammatory markers in the two cohorts. Racial
differences will also be evaluated. Our work has a high translational significance in reducing the disparity in
breast cancer related mortality among AAW by identifying novel preventive strategies for TNBC. Furthermore,
these studies will lead to discovery of novel agents that could help women who are unable to breastfeed to
reduce the risk of developing TNBC.
项目摘要
这项建议的长期目标是减少发展为侵袭性三阴性乳腺癌的风险
癌症(TNBC),特别是非洲裔美国妇女(AAW),通过发现如何延长母乳喂养
保护乳房免受这种风险。AAW的母乳喂养率较低,这可能导致
TNBC发病率和死亡率较高。因此,我们的工作将专门针对乳房的这种差异,
AAW面临的癌症后果。我们开发了独特的小鼠模型,用于研究逐渐退化(GI-
延长母乳喂养)与突然退化(AI-短母乳喂养)乳腺。我们已经表明
乳腺上皮细胞区室的细胞组成发生显著变化,
炎症标志物,重要的是在120天内观察到癌前增生性病变
在产后的人工智能腺中。这些癌前腺体高度表达转录因子Elf 5,这是一个关键的转录因子。
由管腔祖细胞(TNBC的起源细胞)表达的基因。基于这些研究,我们假设
缺乏母乳喂养不仅会改变细胞组成,增加炎症,
通过Elf 5介导的异常分化发展TNBC的风险更高:在本提案中,我们将使用
创新的方法,包括新的小鼠模型和患者样本,以描述
母乳喂养和TNBC。目的1A:描述GI与AI在人类乳腺癌小鼠模型中的保护作用
癌1B.确定阻断雌激素信号传导是否会消除AI诱导的增生性变化。我们
将使用MMTV-Cre; Brca 1fl/fl; p53 fl/fl小鼠和化学致癌物诱导模型来评估AI是否加速
TNBC的肿瘤发病率和进展。我们将用他莫昔芬治疗AI小鼠,以评估是否进展到
增生减轻。目的2:阐明Elf 5的作用和导致细胞凋亡的微环境(ME)的改变。
与AI乳腺癌前病变的关系我们将使用乳腺特异性Elf 5条件
敲除小鼠模型和用于该目的的体外方法。基因表达和CHIP-Seq将用于
识别Elf 5的下游效应子。我们将确定AI与GI之间ME的差异
腺体,特别是不同类型的巨噬细胞的招募。目的3:观察组织学和
使用从母乳喂养的经产妇女获得的人乳腺组织在小鼠中观察到的分子变化
0-3(AI)对比> 6个月(GI)。我们将从Susan G.适用于Cure®纸巾的科门
Bank研究两个队列中胶原沉积和其他炎症标志物的差异。种族
还将评估差异。我们的工作对缩小
通过确定TNBC的新预防策略,在AAW中发现乳腺癌相关死亡率。此外,委员会认为,
这些研究将导致发现新的药物,可以帮助那些无法母乳喂养的妇女,
降低发展TNBC的风险。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Ramesh K. Ganju其他文献
CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.
非小细胞肺癌中的 CD10/NEP。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:15.9
- 作者:
Ramesh K. Ganju;Mary E. Sunday;Dean G. Tsarwhas;A. Card;M. Shipp - 通讯作者:
M. Shipp
MicroRNA-379-5p attenuates cancer stem cells and reduces cisplatin resistance in ovarian cancer by regulating RAD18/Polη axis
微小 RNA-379-5p 通过调节 RAD18/Polη 轴减弱卵巢癌中的癌症干细胞并降低顺铂耐药性
- DOI:
10.1038/s41419-025-07430-5 - 发表时间:
2025-02-27 - 期刊:
- 影响因子:9.600
- 作者:
Devendra Shukla;Sanjay Mishra;Tanima Mandal;Manish Charan;Ajeet Kumar Verma;Md Maqsood Ahamad Khan;Nabanita Chatterjee;Amit Kumar Dixit;Senthil Kumar Ganesan;Ramesh K. Ganju;Amit Kumar Srivastava - 通讯作者:
Amit Kumar Srivastava
Erratum to: miR-29b defines the pro-/anti-proliferative effects of S100A7 in breast cancer
- DOI:
10.1186/s12943-015-0451-9 - 发表时间:
2015-11-16 - 期刊:
- 影响因子:33.900
- 作者:
Helong Zhao;Tasha Wilkie;Yadwinder Deol;Amita Sneh;Akaansha Ganju;Mustafa Basree;Mohd W. Nasser;Ramesh K. Ganju - 通讯作者:
Ramesh K. Ganju
Ramesh K. Ganju的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Ramesh K. Ganju', 18)}}的其他基金
Addressing cancer disparity through defining the molecular link between breast feeding and triple negative breast cancer
通过定义母乳喂养与三阴性乳腺癌之间的分子联系来解决癌症差异
- 批准号:
9888345 - 财政年份:2019
- 资助金额:
$ 43.5万 - 项目类别:
Addressing cancer disparity through defining the molecular link between breast feeding and triple negative breast cancer
通过定义母乳喂养与三阴性乳腺癌之间的分子联系来解决癌症差异
- 批准号:
10590700 - 财政年份:2019
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8526420 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Synthetic cannabinoids as novel therapeutic strategies against non-small cell lun
合成大麻素作为非小细胞肺癌的新型治疗策略
- 批准号:
8294608 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8329625 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8777633 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8841515 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Novel approaches to attenuate lipopolysaccharide-induced inflammation
减轻脂多糖诱导的炎症的新方法
- 批准号:
8291967 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8113028 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
Role of S100A7 in breast cancer progression and metastasis
S100A7 在乳腺癌进展和转移中的作用
- 批准号:
8699159 - 财政年份:2011
- 资助金额:
$ 43.5万 - 项目类别:
相似海外基金
Broadening Participation Research: Understanding faculty attitudes, competency, and perceptions of providing career advising to African American STEM students at HBCUs
扩大参与研究:了解教师对 HBCU 的非裔美国 STEM 学生提供职业建议的态度、能力和看法
- 批准号:
2306671 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Continuing Grant
Cognitive Behavioral Faith-based Depression Intervention For African American Adults (CB-FAITH): An Effectiveness And Implementation Trial
非裔美国成年人基于认知行为信仰的抑郁干预 (CB-FAITH):有效性和实施试验
- 批准号:
10714464 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
DELINEATING THE ROLE OF THE HOMOCYSTEINE-FOLATE-THYMIDYLATE SYNTHASE AXIS AND URACIL ACCUMULATION IN AFRICAN AMERICAN PROSTATE TUMORS
描述同型半胱氨酸-叶酸-胸苷酸合成酶轴和尿嘧啶积累在非裔美国人前列腺肿瘤中的作用
- 批准号:
10723833 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Exploring PTSD Symptoms, Barriers and Facilitators to Mindfulness-based Stress Reduction for Justice-Involved Black/African American Female Adolescents and Parents/Caregivers
探索创伤后应激障碍 (PTSD) 症状、障碍和促进因素,为涉及正义的黑人/非裔美国女性青少年和父母/照顾者进行基于正念的减压
- 批准号:
10593806 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Preventing Firearm Suicide Deaths Among Black/African American Adults
防止黑人/非裔美国成年人因枪支自杀死亡
- 批准号:
10811498 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
BCSER - PVEST: A Dynamic Framework for Investigating STEM Interest, Attitude and Identity Among African American Middle School Students
BCSER - PVEST:调查非裔美国中学生 STEM 兴趣、态度和身份的动态框架
- 批准号:
2327055 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Standard Grant
Making the Connection: Understanding the dynamic social connections impacting type 2 diabetes management among Black/African American men
建立联系:了解影响黑人/非裔美国男性 2 型糖尿病管理的动态社会联系
- 批准号:
10782674 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Building a Community-Based Mental Health Literacy Intervention for African American Young Adults
为非裔美国年轻人建立基于社区的心理健康素养干预措施
- 批准号:
10738855 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
African American Literature in "post" Post-Racial America
“后”后种族美国中的非裔美国文学
- 批准号:
23K00376 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Impact of a Race-Based Stress Reduction Intervention on Well-Being, Inflammation, and DNA methylation in Older African American Women at Risk for Cardiometabolic Disease
基于种族的减压干预措施对有心血管代谢疾病风险的老年非洲裔美国女性的健康、炎症和 DNA 甲基化的影响
- 批准号:
10633624 - 财政年份:2023
- 资助金额:
$ 43.5万 - 项目类别: