Kuang Shao-Qing, Liao Lan, Wang Shu, Medina Daniel, O'Malley Bert W, Xu Jianming
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2005 Sep 1;65(17):7993-8002. doi: 10.1158/0008-5472.CAN-05-1179.
Amplified in breast cancer 1 (AIB1; steroid receptor coactivator-3, p/CIP, RAC3, ACTR, TRAM-1, or NCoA-3) is a transcriptional coactivator for nuclear receptors and certain other transcription factors and is a newly defined oncogene overexpressed in human breast cancer. Although the role and molecular mechanism of AIB1 in normal physiology and in breast cancer are currently under intensive investigation, the role of AIB1 in determination of the susceptibility of mammary gland to chemical carcinogens remains uncharacterized. In this study, we used back-crossed FVB wild-type (WT) and AIB1 mutant mice to assess the role of AIB1 in mammary gland development and in carcinogen-induced tumorigenesis. We show that mammary ductal growth was delayed in AIB1-/- mice with FVB strain background, and mammary ductal outgrowths emanating from the AIB1-/- mammary epithelial transplants in WT mice also were attenuated, indicating that the role of AIB1 in mammary ductal growth is a mammary epithelial autonomous function. In mice treated with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), AIB1 deficiency protected the mammary gland, but not the skin, from tumorigenesis. AIB1 deficiency suppressed the up-regulation of the insulin receptor substrate (IRS)-1 and IRS-2 and thereby inhibited the activation of Akt, expression of cyclin D1, and cell proliferation. The suppression of these components for insulin-like growth factor-I signaling might be partially responsible for the decreased DMBA-induced mammary tumor initiation and progression in AIB1-/- mice. Our results suggest that AIB1 may serve as a potential target for prevention of carcinogen-induced breast cancer initiation and for treatment of breast cancer progression.
乳腺癌中扩增基因1（AIB1；类固醇受体辅激活因子-3、p/CIP、RAC3、ACTR、TRAM-1或NCoA-3）是一种核受体和某些其他转录因子的转录辅激活因子，是一种新定义的在人类乳腺癌中过表达的致癌基因。尽管目前正在深入研究AIB1在正常生理学和乳腺癌中的作用及分子机制，但AIB1在确定乳腺对化学致癌物易感性方面的作用仍未明确。在本研究中，我们使用回交的FVB野生型（WT）和AIB1突变小鼠来评估AIB1在乳腺发育和致癌物诱导的肿瘤发生中的作用。我们发现，具有FVB品系背景的AIB1基因敲除小鼠的乳腺导管生长延迟，并且WT小鼠中源自AIB1基因敲除乳腺上皮移植的乳腺导管增生也减弱，这表明AIB1在乳腺导管生长中的作用是乳腺上皮自主功能。在用化学致癌物7,12-二甲基苯并[a]蒽（DMBA）处理的小鼠中，AIB1缺陷可保护乳腺而非皮肤免受肿瘤发生。AIB1缺陷抑制胰岛素受体底物（IRS）-1和IRS-2的上调，从而抑制Akt的激活、细胞周期蛋白D1的表达和细胞增殖。胰岛素样生长因子-I信号通路这些成分的抑制可能部分导致AIB1基因敲除小鼠中DMBA诱导的乳腺肿瘤起始和进展减少。我们的结果表明，AIB1可能是预防致癌物诱导的乳腺癌起始和治疗乳腺癌进展的潜在靶点。
