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.
项目概要
该提案的长期目标是降低患侵袭性三阴性乳腺癌的风险
癌症 (TNBC),尤其是非裔美国女性 (AAW),通过发现母乳喂养时间的长短
保护乳房免受这种风险。 AAW 的母乳喂养率较低,这可能导致母乳喂养率较高
TNBC 的发生率和死亡率较高。因此,我们的工作将专门解决乳房的这种差异
AAW 面临的癌症结果。我们开发了独特的小鼠模型来研究逐渐退化(GI-
长时间母乳喂养)与乳腺突然退化(AI-短母乳喂养)。我们已经展示了
乳腺上皮细胞区室的细胞组成发生巨大变化,并且整体变化
炎症标志物,重要的是在 120 天内观察到癌前增生性病变
产后的 AI 腺体。这些癌前腺体高度表达转录因子 Elf5,这是一个关键的转录因子。
由管腔祖细胞表达的基因,管腔祖细胞是 TNBC 的起源细胞。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并增加炎症,还会导致
通过 Elf5 介导的异常分化产生 TNBC 的风险更高:在本提案中,我们将使用
创新方法,包括新颖的小鼠模型和患者样本,以描绘之间的联系
母乳喂养和 TNBC。目标 1A:描述 GI 与 AI 在人类乳房小鼠模型中的保护作用
癌症。 1B.确定阻断雌激素信号传导是否会消除 AI 引起的增生性变化。我们
将使用 MMTV-Cre;Brca1fl/fl;p53fl/fl 小鼠和化学致癌物诱导模型来评估 AI 是否加速
TNBC 的肿瘤发生率和进展。我们将用他莫昔芬治疗 AI 小鼠,以评估是否进展为
增生减轻。目标 2:阐明 Elf5 的作用以及导致微环境 (ME) 的改变
AI 乳腺中观察到的癌前变化。我们将使用乳腺特异性 Elf5 条件
敲除小鼠模型和用于此目的的体外方法。基因表达和 CHIP-Seq 将用于
确定 Elf5 的下游效应器。我们将确定 AI 与 GI 之间 ME 的差异
腺体,特别是不同类型巨噬细胞的招募。目标 3:验证组织学和
使用从母乳喂养的经产妇女获得的人类乳腺组织在小鼠中观察到的分子变化
0-3 (AI) vs. > 6 个月 (GI)。我们将从 Susan G. Komen 处获取 FFPE 乳腺组织用于 Cure® Tissue
银行研究两个队列中胶原蛋白沉积和其他炎症标志物的差异。种族
还将评估差异。我们的工作对于缩小贫富差距具有重要的转化意义
通过确定新的 TNBC 预防策略,AAW 中乳腺癌相关死亡率。此外,
这些研究将导致新药物的发现,可以帮助无法母乳喂养的妇女
降低患 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)
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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
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{{ 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:
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:
8841515 - 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:
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