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.
项目总结
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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