Genetic Mapping of Breast Cancer Risk in the Tumor Microenvironment

肿瘤微环境中乳腺癌风险的基因图谱

• 批准号: 9040122
• 负责人: Michael John Flister
• 金额: $ 35.17万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040122
• 关键词: Affect; Age of Onset; Automobile Driving; Backcrossings; Biological Assay; Blood; Blood Circulation; Blood Vessels; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Breeding; Cancer Model; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 3; Congenic Strain; Consomic Strain; Data; Detection; Disease-Free Survival; Distal; Female; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Goals; Growth; Health; Hematogenous; Heritability; Human; Immunity; Implant; In Vitro; Inbred BN Rats; Inbred Strain; Incidence; Link; Luciferases; Lung; Lymphatic; MDA MB 231; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Maps; Measures; Mediating; Metastatic Neoplasm to the Lung; Molecular Genetics; Neoplasm Circulating Cells; Neoplasm Metastasis; Non-Malignant; Pathway interactions; Phenotype; Prognostic Marker; Property; Proteins; Quantitative Trait Loci; Rattus; Recombinants; Risk; Risk Factors; Role; Sequence Analysis; Severe Combined Immunodeficiency; Signal Pathway; Site; Testing; Time; Tissues; Transcript; Tube; Tumor Suppressor Proteins; Tumorigenicity; Variant; WNT Signaling Pathway; Xenograft Model; Xenograft procedure; angiogenesis; base; cancer cell; cancer risk; clinically relevant; comparative; congenic; consomic; density; genetic element; genetic risk factor; genetic variant; in vivo; insight; malignant breast neoplasm; matrigel; member; migration; neoplastic cell; novel; programs; research study; risk variant; tool; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; vasculogenesis

 DESCRIPTION (provided by applicant): Breast cancer is the most prevalent female malignancy and is highly heritable, yet the majority of breast cancer risk remains undefined. Heritable factors underlie most aspects of breast cancer risk [e.g., incidence, age-of- onset, metastatic progression, and disease-free survival]. In addition to variants that impact tumor cells directly (i.e., tumorigenicity), heritability is implicated in multiple components of the tumor microenvironment [e.g., tissue remodeling, angiogenesis, and immunity], which also impact tumorigenesis and progression. However, the genetic variant(s) underlying differences in the tumor microenvironment have rarely been the focus of genetic mapping studies and as such, remain poorly defined. Our goal is to develop a new genetic model to assess breast cancer risk in the tumor microenvironment. We have developed a new model of breast cancer (termed the Consomic Xenograft Model - CXM) that focuses on genetic mapping of strain-specific variant(s) that impact tumor progression through the tumor microenvironment. A consomic rat is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain by selective breeding. Thus, observed phenotypes can be linked to single chromosomes and then further elucidated by comparative sequence analysis and/or selective backcrossing to yield smaller congenics. In CXM, the consomic and parental strains are converted to SCID (severe combined immunodeficiency), so that orthotopically xenografted human breast cancer cells can be tested in vivo. Because the human breast cancer cells are not varied between strains, any differences in breast cancer progression (e.g., primary site growth, vasculogenesis, and distal metastasis) are due solely to genetic differences in the tumor microenvironment, not the malignant cancer cells. CXM utilizes transgenically tagged human cancer cells with defined properties (e.g., triple-negative, pro-metastatic, etc.). Thus, it enables testing of clinically relevant cancer models in strain backgrounds with varying genetic predispositions to breast cancer. Using CXM, we found that BN-derived genetic variant(s) on rat chromosome 3 significantly suppress tumor growth and hematogenous metastasis, whereas lymphatic vasculature and lymphogenous metastasis were completely unaffected. We hypothesize that decreased tumor growth and hematogenous metastasis are due to alterations in the tumor blood vasculature caused by the genetic variant(s) on BN rat chromosome 3. To test this hypothesis and elucidate the genetic mechanism(s), we propose to (1) narrow the causative gene(s) and characterize the underlying mechanism(s) that inhibit breast cancer progression using CXM analysis of two breast cancer cell lines; (2) identify the blood vessel-specific genetic and molecular mechanism(s) that alter tumor blood vasculature and hematogenous metastasis in the SSBN3IL2R consomic rat; and (3) test the role of the WISP2/WNT signaling pathway in decreased breast cancer risk in the SSBN3IL2R consomic rat. These studies will provide mechanistic insight to the role of the tumor microenvironment in breast cancer risk.

 描述（由申请人提供）：乳腺癌是最常见的女性恶性肿瘤，具有高度遗传性，但大多数乳腺癌风险仍不明确。遗传因素是乳腺癌风险的大多数方面的基础[例如，发病率、发病年龄、转移进展和无病生存期]。除了影响肿瘤细胞的变异之外， 直接（即，致瘤性），遗传性涉及肿瘤微环境的多个组分[例如，组织重塑、血管生成和免疫]，其也影响肿瘤发生和进展。然而，肿瘤微环境差异背后的遗传变异很少成为遗传图谱研究的焦点，因此仍然定义不清。我们的目标是开发一种新的遗传模型来评估肿瘤微环境中的乳腺癌风险。我们开发了一种新的乳腺癌模型（称为Consomic Xenograft Model - CXM），其重点是通过肿瘤微环境影响肿瘤进展的菌株特异性变体的遗传图谱。同体大鼠是通过选择性育种将整个染色体渗入到另一近交系的等基因背景中的大鼠。因此，观察到的表型可以与单染色体相关联，然后通过比较序列分析和/或选择性回交来进一步阐明，以产生较小的同源基因。在CXM中，同源体和亲本菌株转化为SCID（严重联合免疫缺陷），以便可以在体内测试原位异种移植的人乳腺癌细胞。因为人乳腺癌细胞在菌株之间没有变化，所以乳腺癌进展的任何差异（例如，原发部位生长、血管生成和远端转移）仅仅是由于肿瘤微环境中的遗传差异，而不是恶性癌细胞。CXM利用具有确定性质（例如，三阴性、促转移等）。因此，它能够在具有不同乳腺癌遗传易感性的菌株背景中测试临床相关的癌症模型。使用CXM，我们发现大鼠3号染色体上BN衍生的遗传变体显著抑制肿瘤生长和血行转移，而淋巴管系统和淋巴转移完全不受影响。我们推测，肿瘤生长和血行转移的减少是由于BN大鼠3号染色体上的遗传变异引起的肿瘤血管系统的改变。为了验证这一假设并阐明遗传机制，我们提出（1）使用两种乳腺癌细胞系的CXM分析来缩小致病基因并表征抑制乳腺癌进展的潜在机制;（2）鉴定改变SSBN 3 IL 2 R单染色体大鼠中肿瘤血管和血行转移的血管特异性遗传和分子机制;以及（3）测试WISP 2/WNT信号传导途径在SSBN 3 IL 2 R嵌合体大鼠中降低乳腺癌风险中的作用。这些研究将为肿瘤微环境在乳腺癌风险中的作用提供机制性见解。