MMPs & Genomic Instability in Mammary Tumor Development

描述(申请人提供)：乳腺癌是美国女性最常见的癌症形式。了解从正常细胞到肿瘤再到转移过程中的基本分子标志物将有助于治疗这种疾病，但这些过程仍然知之甚少。肿瘤是由经历多个基因组突变的单个细胞产生的。最初的突变是如何产生的？是环境导致突变，还是创造了促进突变积累的环境？细胞外基质蛋白，如基质金属蛋白酶(MMPs)，有助于肿瘤的进展。基质金属蛋白酶-3/基质分解素-1参与促进小鼠乳腺增生和癌症；在人类乳腺癌中表达上调，其过表达促进基因组的不稳定。在提出的研究中，我将阐述基因组不稳定在癌症进展中的机制。这项建议涵盖的具体目标如下： (1)检测基质金属蛋白酶-3对乳腺干细胞分化的影响。最近的研究表明，祖细胞可能是肿瘤的前体细胞。 (2)确定基质金属蛋白酶-3是否影响乳腺肿瘤发生的突变率。 (3)检测细胞凋亡在基因组不稳定及基质金属蛋白酶-3依赖的乳腺肿瘤进展中的作用。

DESCRIPTION (provided by applicant): Breast carcinoma is the most common form of cancer in women in the United States. Understanding the basic molecular markers during the transitions from normal cell to carcinoma to metastases will be helpful in treating the disease, but these processes still are poorly understood. Tumors arise from individual cells that undergo multiple genomic mutations. How do the initial mutations arise? Does the environment cause mutations or create an environment that promotes their accumulation? Extracellular matrix proteins, such as matrix metalloproteinases (MMPs), contribute to tumor progression. MMP-3/Stromelysin-1 has been shown to be involved in promoting mammary hyperplasia and cancer in mice; it is upregulated in human breast cancer, and its overexpression promotes genomic instability. In the research proposed, I will address the mechanism of genomic instability in cancer progression. The specific aims to be covered in this proposal are the following: (1) Examine the effect of MMP-3 on mammary stem cell differentiation. Recent work suggests that progenitor cells may be tumor precursors. (2) Determine if MMP-3 affects the rate of mutagenesis in mammary tumor development. (3) Examine effect of apoptosis on generating genomic instability and on MMP-3-dependent mammary tumor progression.