Hormonal Regulation of Breast Cancer

乳腺癌的激素调节

• 批准号: 8369934
• 负责人: Jeffrey Mark Rosen
• 金额: $ 70.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369934
• 关键词: Adenoviruses; Alleles; Alveolar Cell; Award; Biological Models; Biology; Breast; Breast Diseases; Cell Proliferation; Cell Transplantation; Cells; Chimera organism; Clinic; Clinical; Collaborations; Development; Dimerization; Disease; Ductal; Ductal Epithelial Cell; Epithelial Cells; FGFR1 gene; FGFR2 gene; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Foundations; Funding; Gene Targeting; Genetic; Goals; Grant; Growth Factor; Hormones; Human; In Situ; Kinetics; Knock-out; Laboratories; Ligands; Mammary gland; Mediating; Mediator of activation protein; Modeling; Molecular; Morphogenesis; Mus; National Cancer Institute; Neoplasm Metastasis; Pathway interactions; Philosophy; Population; Pregnancy; Premalignant; Program Review Group; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Recurrence; Reporter; Research; Resistance; Role; Signal Transduction; Signal Transduction Pathway; Staging; Stem cells; System; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translational Regulation; Translational Research; Translations; Transplantation; Untranslated RNA; Woman; Work; anticancer research; autocrine; cancer stem cell; developmental genetics; experience; gain of function; hormone regulation; in vivo; lentivirally transduced; loss of function; malignant breast neoplasm; mammary gland development; mouse model; novel; paracrine; prevent; progenitor; research study; self-renewal; stem; stem cell biology; steroid hormone; success

DESCRIPTION (provided by applicant): This is a competing renewal application of a MERIT award currently in its 36th year of funding. The long-term objectives of these studies have been to elucidate the mechanisms by which systemic hormones and local growth factors regulate the normal development of the mammary gland, and to determine how these regulatory mechanisms have deviated in breast cancer. More than a decade ago our laboratory and others presented evidence that steroid hormone-induced proliferation of mammary ductal epithelial cells was regulated by paracrine mechanisms. Recent studies have indicated that steroid hormone regulation of mammary stem and progenitor cells in both the normal mammary gland and luminal breast cancers is also mediated by local paracrine mechanisms involving Wnts, fibroblast growth factors and Rank ligand. Our current studies combine gain- and loss-of function mouse genetic experiments using transgenic, conditional knockout, and lentivirally-transduced mammary epithelial cells and transplantation into the cleared mammary fat pad with the in situ analysis of signal transduction pathways. They will continue to focus on the understanding of both paracrine, juxtacrine and autocrine mechanisms of cell fate determination in the murine mammary gland with emphasis on the mechanisms regulating stem/progenitor cell self-renewal, normal ductal morphogenesis, and early progression in breast cancer. To accomplish these goals we propose: 1. To elucidate the role of the canonical and non-canonical Wnt pathways in mammary stem/progenitor cell self-renewal and survival. 2. To elucidate the molecular mechanisms of FGFR 1 and FGFR2 action on mammary stem and progenitor cells. 3. To understand the mechanisms of Wnt and Fgf pathway cooperativity in mammary stem/progenitor self- renewal and how these are altered in breast cancer. 4. To delineate the role of specific C/EBPss protein isoforms in both stem cell self-renewal and luminal/alveolar cell fate determination 5. To elucidate the role of noncoding RNAs(ncRNAs) in mammary gland development and breast cancer. "Our understanding of the biology and developmental genetics of the normal mammary gland is a barrier to progress...a more complete understanding of the normal mammary gland at each stage of development....will be a critical underpinning of continued advances in detecting, preventing and treating breast cancer" PUBLIC HEALTH RELEVANCE: Approximately 1 in 8 women will be stricken by breast cancer in their lifetime. Discovering the mechanisms by which hormones regulate normal mammary stem and progenitor cells will be critical to our understanding of the alterations which occur both during both the initiation of breast cancer, as well as during cancer metastasis and disease recurrence.

描述（由申请人提供）：这是目前在其第36年的资金中竞争的续约申请。这些研究的长期目标是阐明系统性激素和局部生长因子调节乳腺正常发育的机制，并确定这些调节机制在乳腺癌中的偏差。十多年前，我们的实验室和其他人提供了证据表明，旁分泌机制调节了类固醇激素诱导的乳腺导管上皮细胞的增殖。最近的研究表明，正常乳腺和腔内乳腺癌中乳腺干细胞和祖细胞的类固醇激素调节还通过涉及WNT，成纤维细胞生长因子和秩配体的局部旁分泌机制介导。 我们目前的研究使用转基因，条件敲除和慢病毒转导的乳腺上皮细胞和移植到清除的乳腺脂肪垫中，以及对信号传输途径的原位分析，结合了功能丧失小鼠基因实验。他们将继续专注于对鼠乳腺中细胞命运测定的旁分泌，近二氨酸和自分泌机制的理解，重点是调节茎/祖细胞自我更新，正常的导管形态发生和乳腺癌早期进展的机制。为了实现这些目标，我们提出：1。阐明规范和非规范WNT途径在乳腺茎/祖细胞细胞自我更新和生存中的作用。 2。阐明FGFR 1和FGFR2作用对乳腺和祖细胞的作用的分子机制。 3。了解乳腺茎/祖细胞自我更新中Wnt和FGF途径协作的机制以及如何改变乳腺癌。 4。描绘特异性C/EBPS蛋白同工型在干细胞自我更新和腔/肺泡细胞命运测定中的作用5。阐明非编码RNA（NCRNA）在乳腺发育和乳腺癌中的作用。 “我们对正常乳腺的生物学和发育遗传学的理解是进步的障碍……对每个发育阶段的正常乳腺有更全面的理解。...将是对检测，预防和治疗乳腺癌的持续进展的关键基础” 公共卫生相关性：一生中，大约有八分之一的妇女将因乳腺癌而受苦。发现激素调节正常乳腺茎和祖细胞细胞的机制对于我们对发生的改变至关重要 在乳腺癌的开始以及癌症转移和疾病复发期间。