Arisi Maria F, Starker Rebecca A, Addya Sankar, Huang Yong, Fernandez Sandra V
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Int J Oncol. 2014 Jun;44(6):1831-42. doi: 10.3892/ijo.2014.2354. Epub 2014 Mar 21.
Retinoids have been used as potential chemotherapeutic or chemopreventive agents because of their differentiative, anti-proliferative, pro-apoptotic and antioxidant properties. We investigated the effect of all trans-retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the MCF-10F human normal breast epithelial cells with high dose of estradiol and consists of four cell lines which show a progressive neoplastic transformation: MCF-10F, normal stage; trMCF, transformed MCF-10F; bsMCF, invasive stage; and caMCF, tumorigenic stage. In 3D cultures, MCF-10F cells form tubules resembling the structures in the normal mammary gland. After treatment with estradiol, these cells formed tubules and spherical masses which are indicative of transformation. Cells that only formed spherical masses in collagen were isolated (trMCF clone 11) and treated with ATRA. After treatment with 10 or 1 µM ATRA, the trMCF clone 11 cells showed tubules in collagen; 10 and 43% of the structures were tubules in cells treated with 10 and 1 µM ATRA, respectively. Gene expression studies showed that 207 genes upregulated in transformed trMCF clone 11 cells were downregulated after 1 µM ATRA treatment to levels comparable to those found in the normal breast epithelial cells MCF-10F. Furthermore, 236 genes that were downregulated in trMCF clone 11 were upregulated after 1 µM ATRA treatment to similar levels shown in normal epithelial cells. These 443 genes defined a signature of the ATRA re-programming effect. Our results showed that 1 µM ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process and antagonistically regulate breast cancer associated genes. The invasive and tumorigenic cells did not show any changes in morphology after ATRA treatment. These results suggest that ATRA could be used as a chemopreventive agent to inhibit the progression of premalignant lesions of the breast.
由于维甲酸具有分化、抗增殖、促凋亡和抗氧化特性，它们已被用作潜在的化疗或化学预防剂。我们使用乳腺癌进展的体外模型研究了全反式维甲酸（ATRA）在肿瘤转化不同阶段的作用。该模型先前通过用高剂量雌二醇处理MCF-10F人正常乳腺上皮细胞而建立，由四个显示渐进性肿瘤转化的细胞系组成：MCF-10F，正常阶段；trMCF，转化的MCF-10F；bsMCF，侵袭阶段；和caMCF，致瘤阶段。在三维培养中，MCF-10F细胞形成类似于正常乳腺结构的小管。用雌二醇处理后，这些细胞形成了表明转化的小管和球形团块。分离出仅在胶原蛋白中形成球形团块的细胞（trMCF克隆11）并用ATRA处理。用10或1μM ATRA处理后，trMCF克隆11细胞在胶原蛋白中显示出小管；在用10和1μM ATRA处理的细胞中，分别有10%和43%的结构是小管。基因表达研究表明，在转化的trMCF克隆11细胞中上调的207个基因在1μM ATRA处理后下调至与正常乳腺上皮细胞MCF-10F中发现的水平相当。此外，在trMCF克隆11中下调的236个基因在1μM ATRA处理后上调至正常上皮细胞中显示的相似水平。这443个基因定义了ATRA重编程效应的特征。我们的结果表明，1μM ATRA能够在肿瘤形成过程的早期重新分化转化细胞，并拮抗调节乳腺癌相关基因。侵袭性和致瘤性细胞在ATRA处理后形态没有任何变化。这些结果表明，ATRA可作为化学预防剂用于抑制乳腺癌前病变的进展。
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