REGULATION OF HOX GENE EXPRESSION IN HUMAN BREAST CANCER

视黄酸（RA）对许多细胞过程有深远的影响， 包括胚胎模式形成和细胞分化。ra可 还调节多种癌前病变的生长和分化， 和肿瘤细胞类型。最近的研究表明，RA发挥抗- 对乳腺癌细胞致瘤性和生长抑制作用 线，并在各种其他类型的癌症，包括鳞状细胞癌， 头颈部癌和宫颈癌。虽然确切的 视黄酸可以作为形态发生剂，致畸剂， 和抗肿瘤剂还不清楚， 在分化诱导期间和在 胚胎发生其中一个基因Hoxa-1是同源异型盒基因的成员， 家人Hoxa-1首先从RA-制备的cDNA文库中分离得到。 处理的F9鼠胚胎癌细胞系。Hoxa-1的表达 RA以不依赖蛋白质合成的方式上调基因表达 表明Hoxa-1基因是RA的主要靶基因。 此外，RA响应增强子在3 '区中被鉴定， Hoxa-1基因，这种RA应答增强子与在Hoxa-1基因中发现的相同。 RAR-β基因这些发现表明RA直接调节 转录至少一个同源框基因Hoxa-1。最近， 几个研究小组报道了Hoxa-1在两种组织中的异常高表达， 人乳腺癌细胞系和小鼠乳腺肿瘤。它还 RA仅在人乳腺癌中具有抑制细胞生长的作用 具有功能性雌激素受体的细胞系。目前尚不清楚 Hoxa-1基因在乳腺癌细胞中是如何调节的， Hoxa-1的异常表达与 乳腺癌上皮细胞雌激素受体的表达 在本研究中，我计划研究Hoxa-1基因的调控 在乳腺癌细胞中的表达。具体而言，我将：l）检查 Hoxa-1基因在正常与恶性乳腺上皮细胞中的表达，2） 确定Hoxa-1基因的基因组调控序列， 参与或需要其在乳腺异常高表达 癌细胞系，3）定义精确的调控序列， 参与乳腺中Hoxa-1基因的异常表达 癌细胞系，4）研究表达的调节， Hoxa-1基因在乳腺癌转基因小鼠模型中的应用 发展这些实验应该提供重要的见解， 乳腺癌细胞中Hoxa-1基因的调控。

Retinoic acid (RA) exerts profound effects on many cellular processes, including embryonic pattern formation and cellular differentiation. RA can also regulate the growth and differentiation of a variety of pre-malignant and neoplastic cell types. Recent studies have shown that RA exerts anti- tumorigenic and growth inhibitory effects both in mammary carcinoma cell lines, and in a variety of other types of cancers, including squamous carcinoma of the head and neck, and of the cervix. Although the exact mechanisms by which retinoic acid can function as morphogen, a teratogen, and an anti-tumorigenic agent are not understood, a number of genes are regulated by RA during the induction of differentiation and during embryogenesis. One such gene Hoxa-1, is a member of the homeobox gene family. Hoxa-1 was first isolated from a cDNA library made from an RA- treated F9 murine embryonic carcinoma cell line. Expression of the Hoxa-1 gene is up-regulated by RA in a protein synthesis-independent fashion which indicates that the Hoxa-1 gene is a primary target gene of RA. Moreover, an RA-responsive enhancer was identified in the 3' region of the Hoxa-1 gene, and this RA responsive enhancer is identical to that found in the RAR-beta gene. These findings indicate that RA directly regulates the transcription of at least one of the homeobox genes, Hoxa-1. Recently, several groups have reported abnormally high Hoxa-1 expression in both human breast carcinoma cell lines and mouse mammary tumors. It has also been shown that RA can inhibit cell growth only in human breast carcinoma cell lines which possess a functional estrogen receptor. It is not clear how the Hoxa-1 gene is regulated in the breast carcinoma cells, and whether there is any correlation between aberrant Hoxa-1 expression and expression of estrogen receptor among malignant breast epithelial cells. In this proposal, I plan to investigate the regulation of Hoxa-1 gene expression in breast carcinoma cells. Specifically, I will: l) examine the Hoxa-1 gene expression in normal vs. malignant breast epithelial cells, 2) determine the genomic regulatory sequences of the Hoxa-1 gene that are involved in or required for its aberrantly high expression in breast cancer cell lines, 3) define the precise regulatory sequences that are involved in the aberrant expression of the Hoxa-1 gene in the breast cancer cell lines, 4) investigate the regulation of the expression of the Hoxa-1 gene in a transgenic mouse model system for breast tumor development. These experiments should provide important insights into the regulation of the Hoxa-1 gene in breast cancer cells.