High collagen density favors pro-tumorigenic prolactin actions in breast cancer

高胶原蛋白密度有利于乳腺癌中促肿瘤催乳素的作用

• 批准号: 8645161
• 负责人: Craig Barcus
• 金额: $ 3.12万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2016-08-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645161
• 关键词: Achievement; Acinus organ component; Affect; Animals; Area; Automobile Driving; Behavior; Biochemistry; Biology; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Carcinoma; Cancer Biology; Carcinoma; Cellular biology; Characteristics; Collagen; Communication; Complex; Conflict (Psychology); Development; Disease; Extracellular Matrix; Faculty; Family; Fellowship; Female; Focal Adhesion Kinase 1; Focal Adhesions; Future; Gelatinase A; Goals; Guanosine Triphosphate; In Vitro; Incidence; Integrin beta Chains; Integrins; Investigation; JAK2 gene; Journals; Lead; Light; Literature; MAP2K1 gene; MAPK3 gene; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Membrane Microdomains; Mentors; Mentorship; Mitogen-Activated Protein Kinase 3; Molecular; Monitor; Mus; Neoplasm Metastasis; Oncogenic; Organism; Outcome; PRLR gene; Pathway interactions; Phosphotransferases; Physiological; Prolactin; Prolactin Receptor; Relative (related person); Reporting; Research; Research Personnel; Role; STAT5A gene; Scientist; Signal Pathway; Signal Transduction; System; Testing; Thinking; Training; Transgenic Mice; Translating; Transplantation; Tumor Cell Line; Up-Regulation; Woman; breast density; cell behavior; density; design; functional outcomes; in vivo; malignant breast neoplasm; mouse model; novel therapeutics; pregnant; public health relevance; receptor; research study; responsible research conduct; scaffold; therapeutic target; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Prolactin (PRL) involvement in breast cancer progression is increasingly recognized, yet its actions are poorly understood. Clinically, circulating PRL levels and density of the extracellular matrix (ECM) alone are significant risk factors for breast cancer. In mouse models, PRL promotes mammary carcinomas that resemble aggressive luminal breast cancers in women, and increased collagen density promotes tumor metastasis and progression. Although recent studies are illuminating the contributions of the ECM to the physiological actions of prolactin, little is known about the functional relationship between ECM density and PRL signaling in breast cancer. Here, our goal is to elucidate the interaction between collagen density and PRL signaling in breast cancer progression. In this revised application, I will test the hypothesis that PRL and stiff collagen matrices interact to promote mammary tumorigenesis and progression via association of PRL receptors with beta-integrins and lipid rafts, driving tumorigenic PRL actions through the FAK-SFK-ERK1/2 pathway. Specifically, I will determine the molecular mechanisms that control the interactions between ECM density and PRL signaling in breast cancer cells in a defined in vitro system (Aim 1), and examine the interplay between collagen density and PRL signaling in the development and progression of luminal mammary tumors in vivo, using a PRL transgenic mouse with humanized PRL expression and a genetically modified mouse that mimics the elevated collagen density observed in a subset of women (Aim 2). Achievement of these aims will lead to a more complete understanding of the complex interactions between the ECM and prolactin in breast cancer. This will allow for an informed approach for the development of novel therapeutics that uncouple elevated matrix density from pro-tumorigenic signaling pathways. Achieving the scientific goals of this proposal is only the first step in developing into an independent academic research scientist. Taking advantage of the outstanding facilities, faculty and training opportunities at UW-Madison, as well as the mentorship of my sponsor, I also will grow as an independent investigator in the areas of critical thinking, communication, mentoring and responsible conduct of research. This fellowship will aid in my development as a cancer biologist so that I may establish my own research group to discover new therapeutic and preventative approaches to cancer and train future scientist in cancer and cellular biology.

描述（由申请人提供）：人们越来越认识到催乳素（PRL）参与乳腺癌进展，但对其作用却知之甚少。临床上，循环 PRL 水平和细胞外基质 (ECM) 密度本身就是乳腺癌的重要危险因素。在小鼠模型中，PRL 会促进乳腺癌的发生，类似于女性侵袭性管腔乳腺癌，而胶原蛋白密度的增加会促进肿瘤的转移和进展。尽管最近的研究阐明了 ECM 对催乳素生理作用的贡献，但对于乳腺癌中 ECM 密度和 PRL 信号之间的功能关系知之甚少。在这里，我们的目标是阐明乳腺癌进展中胶原蛋白密度和 PRL 信号之间的相互作用。在这个修订后的申请中，我将测试以下假设：PRL 和硬胶原基质相互作用，通过 PRL 受体与 β-整联蛋白和脂筏的关联，促进乳腺肿瘤的发生和进展，通过 FAK-SFK-ERK1/2 途径驱动致瘤 PRL 作用。具体来说，我将确定在确定的体外系统中控制乳腺癌细胞 ECM 密度和 PRL 信号传导之间相互作用的分子机制（目标 1），并检查胶原蛋白密度和 PRL 信号传导在管腔发育和进展中的相互作用。使用具有人源化 PRL 表达的 PRL 转基因小鼠和模拟在女性亚群中观察到的胶原蛋白密度升高的转基因小鼠（目标 2）。这些目标的实现将使人们更全面地了解乳腺癌中 ECM 和催乳素之间复杂的相互作用。这将为开发新型疗法提供一种明智的方法，将升高的基质密度与促肿瘤信号通路分开。 实现该提案的科学目标只是发展成为独立学术机构的第一步 研究科学家。利用威斯康星大学麦迪逊分校出色的设施、师资和培训机会，以及我的赞助商的指导，我也将在批判性思维、沟通、指导和负责任的研究行为领域成长为一名独立研究者。该奖学金将有助于我作为一名癌症生物学家的发展，以便我可以建立自己的研究小组，发现新的癌症治疗和预防方法，并培训未来的癌症和细胞生物学科学家。