DREAM On, DREAM Off: A Review of the Estrogen Paradox

It is generally assumed that all estrogen receptor positive (ER+) breast cancers proliferate in response to estrogen and therefore examples of estrogen-induced regression of ER+ cancers are paradoxical. This review reexamines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB – MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition respectively suggest that a single hormone, either estrogen, progesterone or androgen could activate the DREAM pathway leading to reversible cell cycle arrest. Conversely, the presence of two hormones, could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema. To investigate estrogen (E2)-induced changes in gene transcription in luminal breast cancer cells with high (MCF7-ER) and low (MCF7-EM) estrogen receptor expression.

学界普遍认为，所有雌激素受体阳性（estrogen receptor positive, ER+）乳腺癌均会响应雌激素而发生增殖，因此雌激素诱导ER+乳腺癌退缩的案例便显得自相矛盾。本综述重新审视了ER+乳腺癌Luminal A亚型的雌激素退缩悖论。
研究表明，乳腺癌对雌激素的增殖响应取决于ER的表达水平。从机制层面而言，一项针对术前雌二醇干预的机遇窗口期研究显示，当ER表达水平较高时，雌二醇可激活DREAM-MMB（二聚化伴侣蛋白、成视网膜细胞瘤样蛋白、E2F4与MuvB——MYB-MuvB）通路以抑制细胞增殖。
在月经周期及围绝经期分别出现的激素波动过程中，乳腺上皮的响应与乳腺癌发病率的变化表明，单一激素（雌激素、孕激素或雄激素）均可激活DREAM通路，进而引发可逆的细胞周期阻滞。反之，当存在两种激素时，DREAM-MMB复合物可转换为促增殖通路。
本研究利用公开数据集，分析了芳香化酶抑制剂与ICI 182,780处理后的基因表达变化，以验证该假说。本综述提出，可将当前针对Luminal A型肿瘤的所有内分泌治疗方案整合至单一理论框架中。
本研究旨在探究雌激素（estrogen, E2）诱导高表达ER（MCF7-ER）与低表达ER（MCF7-EM）的管腔型乳腺癌细胞的基因转录变化。