Molecular Alterations in Lobular/Ductal Breast Cancer

小叶型乳腺癌在形态和临床上都不同于更常见的导管类型。它们在类固醇激素受体表达和增殖率上也存在差异。表现出小叶形态的乳腺癌细胞在等位基因丢失模式和特定途径的成分方面也可能是不同的，如e-钙粘素/连环蛋白和BRCA1/BRCA2介导的DNA修复。很难评估小叶癌的独特特征，大多数研究只能评估这种相对罕见的肿瘤类型中的一小部分。作为NCI资助的病例对照研究的一部分，将收集350多个浸润性小叶和导管乳腺癌的组织样本，并测试乳腺癌相关蛋白的表达，以评估联合激素替代疗法(CHRT)的使用与55-79岁女性浸润性小叶和导管乳腺癌发病率之间的关系。利用研究中收集的组织样本，我们建议1)评估350例浸润性小叶和导管癌中P53等位基因缺失、突变和蛋白过度表达的差异；2)使用新开发的微阵列技术(HuSNP)评估100例小叶和导管癌中全基因组等位基因丢失率的差异。作为母公司研究的一部分，我们正在仔细收集大量数据，这也将使我们能够探索BRCA相关DNA修复成分和e-钙粘附素异常变化对其他肿瘤表型的贡献，如ER和PR阳性或阴性亚组。在一大组小叶和导管癌中进行的全基因组杂合性缺失扫描将提供迄今为止对小叶癌等位基因丢失的最全面的描述。从对大量小叶癌的研究中获得的有关形态特征的信息可能会增加对乳腺癌不同亚型的生物学的了解，为将患者划分为预后和治疗组的研究提供基础，和/或为特定肿瘤类型的靶向治疗的发展提供信息。

Lobular breast cancers differ both morphologically and clinically from the more common ductal type. They also differ in steroid hormone receptor expression and proliferation rates. Breast cancer cells demonstrating a lobular morphology may also be distinct with respect to allelic loss patterns and components of defined pathway, such as e- cadherin/catenin and BRCA1/BRCA2-mediated DNA repair. It has been difficult to assess the unique characteristics of lobular cancer most studies can only evaluate a small number of this relative uncommon tumor type. Over 350 tissue samples each of invasive lobular and ductal breast cancer will be collected and tested for expression of breast cancer- related proteins as part of an NCI-funded case-control study to assess associations between the use of combined hormone replacement therapy (CHRT) and the incidence of both invasive lobular and ductal breast cancer in women aged 55-79. Using the tissue samples collected in the study, we propose to 1) evaluate the difference in the rates of p53 allelic loss, mutation and protein over-expression in 350 each of invasive lobular and ductal cancers and 2) evaluate the difference in the genome- wide rate of allelic loss in 100 each of lobular and ductal cancers using newly developed microarray techniques (HuSNP). The large amount of data that is being carefully collected as part of the parent study will also allow us explore the contribution of alterations in BRCA-related DNA repair components and e-cadherin abnormalities to other tumor phenotypes such as ER and PR positive or negative subgroups. The genome-wide scan for LOH in a large set of lobular and ductal cancers will provide the most comprehensive description of allelic loss on lobular cancer to date. Information about morphology-specific traits gained from studying a large number of lobular cancers could lead to an increased understanding of the biology of distinct subsets of breast cancer, provide a basis for studies that would define patient stratification into prognostic and treatment groups and/or inform the development of targeted therapies for specific tumor types.