Cancer Drug Discovery Laboratory, Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, VIC 3168, Australia.
Breast Cancer Res Treat. 2012 Apr;132(2):765-71. doi: 10.1007/s10549-012-1953-4. Epub 2012 Jan 12.
The main biological active substance secreted by the pineal gland, melatonin (MLT), counteracts the effects of estrogens in breast cancer via exerting a number of its own oncostatic properties. Recent studies of postmenopausal women have identified that the major metabolite of MLT is statistically significantly associated with a lower risk of developing breast cancer. While MLT production decreases with age, breast cancer risk, however, increases with age and obesity. We hypothesize that MLT inhibits estrogen production in breast adipose fibroblasts (BAFs), the main local source of estrogen in breast tumors of postmenopausal women, by inhibiting transcription of the CYP19A1 gene that encodes the key enzyme aromatase. Normal BAFs were cultured from women undergoing breast reduction surgery, while breast cancer-associated fibroblasts (CAFs) were isolated from three women with estrogen receptor (ER) positive invasive ductal carcinomas. MTNR1A and MTNR1B receptor expression and CYP19A1 mRNA expression following MLT treatments were determined by qRT-PCR. BAFs express the G-protein coupled MLT receptors MTNR1A and MTNR1B with elevated levels of MTNR1A found in CAFs. Treatment of BAFs and CAFs with MLT resulted in significant suppression of CYP19A1 transcription and aromatase activity at pharmacological, physiological and sub-physiological concentrations. MLT suppression occurred through promoter-specific PI.4-, PI.3- and PII-derived CYP19A1 mRNA. Stimulation of CYP19A1 PII-mRNA and aromatase activity by prostaglandin E(2) (PGE(2)) were significantly attenuated by physiological doses of MLT. Lower levels of MLT in aging women may increase the risk of progressing ER-positive breast cancer through a decreased ability to suppress CYP19A1 expression and subsequent local estrogen production in BAFs/CAFs.
松果腺分泌的主要生物活性物质褪黑素 (MLT) 通过发挥多种自身的抗肿瘤特性来对抗乳腺癌中的雌激素作用。最近对绝经后妇女的研究表明，MLT 的主要代谢物与较低的乳腺癌发病风险呈统计学显著相关。虽然 MLT 的产生随着年龄的增长而减少，但乳腺癌的风险却随着年龄和肥胖的增加而增加。我们假设 MLT 通过抑制编码关键酶芳香酶的 CYP19A1 基因的转录来抑制乳腺脂肪成纤维细胞 (BAFs) 中雌激素的产生，BAFs 是绝经后妇女乳腺肿瘤中雌激素的主要局部来源。正常的 BAFs 是从接受乳房缩小手术的妇女中培养出来的，而乳腺癌相关成纤维细胞 (CAFs) 则是从 3 名雌激素受体 (ER) 阳性浸润性导管癌妇女中分离出来的。用 qRT-PCR 测定 MLT 处理后 MTNR1A 和 MTNR1B 受体表达和 CYP19A1 mRNA 表达。BAFs 表达 G 蛋白偶联的 MLT 受体 MTNR1A 和 MTNR1B，CAFs 中发现 MTNR1A 水平升高。用 MLT 处理 BAFs 和 CAFs 可显著抑制 CYP19A1 转录和芳香酶活性，在药理学、生理学和亚生理学浓度下。MLT 抑制作用是通过特定于启动子的 PI.4、PI.3 和 PII 衍生的 CYP19A1 mRNA 发生的。生理剂量的 MLT 显著减弱了前列腺素 E2 (PGE2) 对 CYP19A1 PII-mRNA 和芳香酶活性的刺激作用。衰老女性中 MLT 水平降低可能通过降低抑制 CYP19A1 表达和随后在 BAFs/CAFs 中局部产生雌激素的能力，增加 ER 阳性乳腺癌的进展风险。
