Bieche I, Parfait B, Le Doussal V, Olivi M, Rio M C, Lidereau R, Vidaud M
Laboratoire de Génétique Moléculaire-UPRES JE 2195, Faculté des Sciences Pharmaceutiques et Biologiques de Paris, France.
Cancer Res. 2001 Feb 15;61(4):1652-8.
The estrogen receptor (ER) status of breast tumors is used to identify patients who may respond to endocrine agents such as tamoxifen. However, ER status alone is not perfectly predictive, and there is a pressing need for more reliable markers of endocrine responsiveness. Here, we identified the well-known CGA gene (coding for the alpha subunit of glycoprotein hormones) as a new ERalpha-responsive gene in human breast cancer cells. We used a real-time quantitative reverse transcription-PCR assay to quantify CGA mRNA copy numbers in a large series of breast tumors. CGA overexpression (> 10 SD above the mean for normal breast tissues) was observed in 44 of 131 (33.6%) breast tumor RNAs, ranging from 20 to 16,500 times the level in normal breast tissues; the highest levels of CGA gene expression were close to those observed in placenta. Significant links were observed between CGA gene overexpression and Scarff-Bloom-Richardson histopathological grade I+II (P = 0.015), and progesterone (P = 0.0009) and estrogen (P < 10(-7)) receptor positivity, which suggested that CGA is a marker of low tumor aggressiveness. We observed CGA mRNA overexpression in 44 of 90 (48.9%) ERalpha-positive tumors and in none of the 41 ERalpha-negative tumors. Immunohistochemical studies demonstrated that human chorionic gonadotropin alpha protein was strictly limited to ERalpha-positive tumor cells. Overexpression of the CGA gene was not accompanied by overexpression of the CGB gene. Our results also suggest that CGA could be a more reliable marker than PS2 and PR for ERalpha functionality and, thus, for endocrine responsiveness. Moreover, the CGA marker has the added value of dichotomizing ERalpha-positive patients into two subgroups of similar size. Specific antibodies directed to secreted human chorionic gonadotropin alpha protein are commercially available, thus facilitating the future application of this marker to the clinical management of breast cancer.
乳腺肿瘤的雌激素受体（ER）状态用于识别可能对他莫昔芬等内分泌药物有反应的患者。然而，仅ER状态并不能完全预测，因此迫切需要更可靠的内分泌反应性标志物。在此，我们确定了著名的CGA基因（编码糖蛋白激素的α亚基）是人类乳腺癌细胞中一种新的ERα反应基因。我们使用实时定量逆转录PCR分析来量化大量乳腺肿瘤中CGA mRNA的拷贝数。在131个乳腺肿瘤RNA中的44个（33.6%）中观察到CGA过表达（比正常乳腺组织平均值高>10个标准差），范围是正常乳腺组织水平的20至16500倍；CGA基因表达的最高水平接近在胎盘中观察到的水平。在CGA基因过表达与斯卡夫-布鲁姆-理查森组织病理学I+II级（P = 0.015）、孕激素（P = 0.0009）和雌激素（P < 10-7）受体阳性之间观察到显著关联，这表明CGA是低肿瘤侵袭性的标志物。我们在90个ERα阳性肿瘤中的44个（48.9%）中观察到CGA mRNA过表达，而在41个ERα阴性肿瘤中均未观察到。免疫组织化学研究表明，人绒毛膜促性腺激素α蛋白严格局限于ERα阳性肿瘤细胞。CGA基因的过表达并未伴随CGB基因的过表达。我们的结果还表明，对于ERα功能以及内分泌反应性，CGA可能是比PS2和PR更可靠的标志物。此外，CGA标志物具有将ERα阳性患者分为两个大小相似亚组的附加价值。针对分泌的人绒毛膜促性腺激素α蛋白的特异性抗体可商购，从而便于该标志物未来在乳腺癌临床管理中的应用。
