Suzuki T, Hayashi S, Miki Y, Nakamura Y, Moriya T, Sugawara A, Ishida T, Ohuchi N, Sasano H
Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Endocr Relat Cancer. 2006 Mar;13(1):233-50. doi: 10.1677/erc.1.01075.
It has been reported that agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARgamma remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARgamma in 238 human breast carcinoma tissues. PPARgamma immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) alpha, ERbeta, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARgamma immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARgamma immunoreactivity was an independent prognostic factor for overall survival in ERalpha-positive patients. We then examined possible mechanisms of modulation by PPARgamma on estrogenic actions in MCF-7 breast carcinoma cells. A PPARgamma activator, 15-deoxy-Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARgamma antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogen-responsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ(2) in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ(2) significantly inhibited estrogen-mediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARgamma is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.
据报道，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可抑制乳腺癌细胞增殖，但PPARγ在人类乳腺癌中的生物学意义仍未明确。因此，我们对238例人类乳腺癌组织进行了PPARγ免疫定位。在42%的癌组织中检测到PPARγ免疫反应性，且与雌激素受体（ER）α、ERβ、孕激素受体、视黄酸X受体、p21或p27的状态显著相关，与组织学分级或环氧化酶-2状态呈负相关。单因素分析显示，PPARγ免疫反应性与乳腺癌患者临床结局改善显著相关，多因素分析表明，PPARγ免疫反应性是雌激素受体α阳性患者总生存的独立预后因素。然后，我们研究了PPARγ调节MCF-7乳腺癌细胞雌激素作用的可能机制。PPARγ激活剂15-脱氧-Δ（12,14）-前列腺素J2（15d-PGJ2）显著抑制雌二醇在MCF-7细胞中依赖雌激素反应元件的反式激活，添加PPARγ拮抗剂GW9662可阻断该作用。随后，使用定制的聚焦于雌激素反应基因的微阵列进行研究，结果显示，49个基因的mRNA表达受雌二醇显著调节，但在49个基因中的16个（33%）基因中添加15d-PGJ2后，这种显著性消失。这一发现通过对11个基因进行实时PCR得到证实。15d-PGJ2显著抑制雌激素介导的MCF-7细胞增殖，并导致p21和p27蛋白积累。这些结果表明，PPARγ主要表达于高分化和雌激素受体阳性的乳腺癌中，并调节雌激素作用。
