Novel Gene Networks in Breast Development and Cancer

描述（由申请人提供）：控制乳腺复杂的、经尿道调节的生长和发育的基因网络可能涉及异常表达的相同基因，这些基因有助于乳腺癌的发生及其向转移的进展。 因此，该计划项目的总体目标是识别和表征这些基因通路，以定义准确预测临床复发可能性的包容性表达模式，从而可以选择患者接受或避免辅助治疗。 我们发现的几个新的基因网络在正常乳腺发育和癌症进展中发挥作用，将探讨它们的相互作用及其作为治疗和预防靶点的潜力，我们将寻求整合全面的基因扩增和表达信息，结合两种分子分析方法。 具体项目包括：1）整合RNA表达和阵列CGH谱以预测长期乳腺癌进展，使用具有>12年临床随访的冷冻肿瘤标本的独特集合来鉴定指示个体患者肿瘤的转移能力的个体基因途径和综合分子特征; 2）确定SAFB支架附着因子的肿瘤抑制作用，我们已经发现其遗传基因座在乳腺癌中显示出最高的杂合性丢失; 3）靶向IGF-I及其与进展为恶性肿瘤的雌激素途径的相互作用，基于我们的发现和其他发现，即IGF系统组分的激活是有害的，血清IGF-I是乳腺癌的危险因素，并且在IGF和雌激素系统之间存在直接的正反馈; 4）确定Ptc 1 hedgehog受体在乳腺导管发育和进展为瘤形成中的作用，因为我们发现异常Ptc 1导致导管增生，并且hedgehog网络调节可能对转移行为至关重要的功能; 5）研究p190-B RhoGAP相互作用在乳腺发育中的作用，特别是在乳腺脂肪垫中的终末芽的侵袭性生长，以及在乳腺癌的侵袭和转移中的作用。 这些项目将得到病理学和组织资源，生物统计学和阵列分析核心，以及动物处理和成像核心的支持。 这些高度互动的项目旨在提高我们对乳腺发育如何变得恶性和侵袭性的认识，并确定基因扩增和表达谱，这将选择那些可能真正受益于辅助治疗的乳腺癌患者。

DESCRIPTION (provided by applicant): Gene networks controlling the complex, hormonally-regulated growth and development of the mammary gland are likely to involve the same genes which, aberrantly expressed, contribute to the onset of breast cancer and its progression to metastasis. The overall goal of this Program Project is thus to identify and characterize these gene pathways, in order to define inclusive expression patterns that accurately predict the likelihood of clinical recurrence so that patients can be selected to receive or be spared adjuvant therapy. Several novel gene networks which we have found to have roles in normal mammary development and progression to cancer will be explored in terms of their interactions and their potential as targets for treatment and prevention, and we will seek to integrate comprehensive gene amplification and expression information combining two molecular profiling approaches. The individual projects are: 1) integrating RNA expression and array CGH profiles to predict long-term breast cancer progression, using a unique collection of frozen tumor specimens with >12 years clinical follow-up to identify individual gene pathways and comprehensive molecular signatures indicating the metastatic capability of an individual patient's tumor; 2) defining the tumor suppressor role of the SAFB scaffold attachment factors, whose genetic locus we have found to show the highest loss of heterozygosity yet reported in breast cancer; 3) targeting IGF-I and its cross-talk with the estrogen pathway in progression to malignancy, based on our findings and others that activation of IGF system components is prognostically ominous, that serum IGF-I is a breast cancer risk factor, and that there is direct positive feedback between the IGF and estrogen systems; 4) determining the role of the Ptc1 hedgehog receptor in mammary ductal development and progression to neoplasia, since we find that aberrant Ptc1 leads to ductal hyperplasia and that the hedgehog network regulates functions likely to be critical for metastatic behavior; 5) investigate the role of p190-B RhoGAP interactions in mammary development, particularly the invasive growth of the terminal end bud into the mammary fat pad, and also in breast cancer invasion and metastasis. These Projects will be supported by a Pathology and Tissue Resource, a Biostatistics and Array Analysis Core, and Animal Handling and Imaging Core. These highly interactive projects are designed to enhance our knowledge of how mammary development can become malignant and invasive, and to define gene amplification and expression profiles which will select those breast cancer patients who may truly benefit from adjuvant therapy.