Department of Applied Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland.
Molecules. 2020 Mar 13;25(6):1321. doi: 10.3390/molecules25061321.
Breast cancer depends on women's age. Its chemotherapy and hormone therapy lead to the loss of bone density and disruption of the skeleton. The proteins RANK and RANKL play a pivotal role in the formation of osteoclasts. It is also well established that the same proteins (RANK and RANKL) are the main molecules that play an important role in mammary stem cell biology. Mammary stem cells guarantee differentiation of the epithelial mammary cells, the growth of which is regulated by the progesterone-induced RANKL signaling pathway. The crosstalk between progesterone receptor, stimulated by progesterone and its analogues results in RANKL to RANK binding and activation of cell proliferation and subsequently unlimited expansion of the breast cancer cells. Therefore downstream regulation of this signaling pathway is desirable. To meet this need, a new class of selective estrogen receptor modulators (SPRMs) with anti- and mesoprogestin function were tested as potential anti-RANK agents. To establish the new feature of SPRMs, the impact of tested SPRMs on RANK-RANKL proteins interaction was tested. Furthermore, the cells proliferation upon RANKL stimulation, as well as NFkB and cyclin D1 expression, induced by tested SPRMs were analyzed. Conducted experiments proved NFkB expression inhibition as well as cyclin D1 expression limitation under asoprisnil and ulipristal treatment. The established paracrine anti-proliferative activity of antiprogestins together with competitive interaction with RANK make this class of compounds attractive for further study in order to deliver more evidence of their anti-RANK activity and potential application in the breast cancer therapy together with its accompanied osteoporosis.
乳腺癌取决于女性的年龄。其化疗和激素治疗导致骨密度丧失和骨骼破坏。蛋白质 RANK 和 RANKL 在破骨细胞的形成中起着关键作用。同样已经确立的是，相同的蛋白质（RANK 和 RANKL）是在乳腺干细胞生物学中起重要作用的主要分子。乳腺干细胞保证上皮乳腺细胞的分化，其生长受孕激素诱导的 RANKL 信号通路调节。孕激素和其类似物刺激的孕激素受体的串扰导致 RANKL 与 RANK 的结合以及细胞增殖的激活，随后乳腺癌细胞的无限扩增。因此，需要对这种信号通路进行下游调节。为了满足这一需求，测试了具有抗孕激素和中孕激素功能的新型选择性雌激素受体调节剂（SPRMs）作为潜在的抗 RANK 剂。为了确立 SPRMs 的新特征，测试了 SPRMs 对 RANK-RANKL 蛋白相互作用的影响。此外，还分析了 RANKL 刺激后细胞增殖以及由测试的 SPRMs 诱导的 NFkB 和细胞周期蛋白 D1 表达。进行的实验证明了阿索普里斯尼尔和乌利普里斯塔尔治疗下 NFkB 表达的抑制以及细胞周期蛋白 D1 表达的限制。抗孕激素的旁分泌抗增殖活性的建立以及与 RANK 的竞争性相互作用使这类化合物具有吸引力，以便进一步研究其抗 RANK 活性及其在乳腺癌治疗及其伴随的骨质疏松症中的潜在应用提供更多证据。
