MMPs & Genomic Instability in Mammary Tumor Development

描述（由申请人提供）：乳腺癌是美国女性中最常见的癌症。了解从正常细胞到癌再到转移过程中的基本分子标记将有助于治疗该疾病，但这些过程仍然知之甚少。肿瘤产生于单个细胞经历多次基因组突变。最初的突变是如何产生的？环境是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。MMP-3/Stromelysin-1已被证明参与促进小鼠乳腺增生和癌症；它在人类乳腺癌中被上调，它的过度表达促进了基因组的不稳定性。在提出的研究中，我将探讨基因组不稳定性在癌症进展中的机制。本建议的具体目标如下：

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.