Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, 467-8601, Japan.
Breast Cancer Res Treat. 2011 Nov;130(1):331-9. doi: 10.1007/s10549-011-1672-2. Epub 2011 Jul 14.
Estrogen receptor (ER) α is essential for estrogen-dependent growth, and its level of expression is a crucial determinant of response to endocrine therapy and prognosis in ERα-positive breast cancer. Breast cancer patients show a wide range of ERα expression levels and the levels of expression in individual patients change during disease progression and in response to systemic therapies. However, little is known about how the expression of ERα in human breast cancer is regulated. Recently, several microRNAs (miRNAs) that directly target ERα have been identified, and we previously demonstrated that miR-206 expression was downregulated in ERα-positive human breast cancer. In this study, expression levels of miRNAs that directly target ERα, including miR-18a, miR-18b, miR-22, miR-193b, miR-221/222 and miR-302c, were analyzed in human breast cancer samples by quantitative reverse transcription-PCR analysis. Correlations between the expression levels of these miRNAs and clinicopathological factors, including prognosis, were analyzed. miR-18a expression was much higher in ERα-negative than in ERα-positive tumors (P < 0.0001), with the expression levels of miR-18a not differing in ERα-positive breast cancer as a function of ERα protein level. Surprisingly, the expression levels of miR-193b and miR-221 were significantly lower in ERα-negative than in ERα-positive tumors (P = 0.0015 and P = 0.0045, respectively), and the levels of these miRNAs gradually increased as ERα protein expression increased. There was no statistically significant association between miR-22 and ERα expression, and miR-302c expression was minimal in human breast cancer samples. Prognostic analysis showed that low miR-18b expression was significantly associated with improved survival in HER2-negative breast cancer, although miR-18b expression was not correlated with ERα protein expression. Our results suggest that miRNAs that directly target ERα have distinct roles in not only regulating ERα but also regulating other target genes in human breast cancer.
雌激素受体 (ER)α 对于雌激素依赖性生长至关重要，其表达水平是 ERα 阳性乳腺癌对内分泌治疗和预后反应的关键决定因素。乳腺癌患者表现出广泛的 ERα 表达水平，并且个别患者的表达水平在疾病进展过程中以及对全身治疗的反应中会发生变化。然而，人们对 ERα 在人乳腺癌中的表达如何受到调控知之甚少。最近，已经鉴定出几种直接靶向 ERα 的 microRNAs（miRNAs），我们之前证明 miR-206 在 ERα 阳性的人乳腺癌中表达下调。在这项研究中，通过定量逆转录-PCR 分析分析了直接靶向 ERα 的 miRNAs（包括 miR-18a、miR-18b、miR-22、miR-193b、miR-221/222 和 miR-302c）在人乳腺癌样本中的表达水平。分析了这些 miRNA 的表达水平与包括预后在内的临床病理因素之间的相关性。miR-18a 在 ERα 阴性肿瘤中的表达明显高于 ERα 阳性肿瘤（P<0.0001），而在 ERα 阳性乳腺癌中，miR-18a 的表达水平与 ERα 蛋白水平无关。令人惊讶的是，miR-193b 和 miR-221 在 ERα 阴性肿瘤中的表达明显低于 ERα 阳性肿瘤（P=0.0015 和 P=0.0045），并且随着 ERα 蛋白表达的增加，这些 miRNA 的水平逐渐升高。miR-22 与 ERα 表达之间没有统计学上的显著相关性，而 miR-302c 在人乳腺癌样本中的表达微不足道。预后分析表明，在 HER2 阴性乳腺癌中，miR-18b 表达水平低与生存改善显著相关，尽管 miR-18b 表达与 ERα 蛋白表达无关。我们的结果表明，直接靶向 ERα 的 miRNAs 在调节 ERα 以及调节人乳腺癌中的其他靶基因方面具有不同的作用。
