MMPs & Genomic Instability in Mammary Tumor Development

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症形式。 了解从正常细胞到癌再到转移的转变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。 肿瘤产生于经历多个基因组突变的单个细胞。最初的突变是如何产生的？ 是环境导致突变还是创造了一个促进突变积累的环境？ 细胞外基质蛋白，如基质金属蛋白酶（MMP），有助于肿瘤的进展。 MMP-3/基质溶解素-1已被证明参与促进小鼠的乳腺增生和癌症;它在人乳腺癌中上调，并且其过表达促进基因组不稳定性。 在这项研究中，我将讨论癌症进展中基因组不稳定性的机制。 本提案所涉具体目标如下： (1)检测MMP-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。 (2)确定MMP-3是否影响乳腺肿瘤发展中的诱变率。 (3)检查细胞凋亡对产生基因组不稳定性和MMP-3依赖性乳腺肿瘤进展的影响。

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.