Mechanisms of breast cancer progression and invasion, often involve alteration of hormonal signaling, and upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Herein, we describe a rationally designed first-in-class novel small molecule inhibitor for targeting oncogenic and hormonal signaling in ER-positive breast cancer. BC-N102 treatment exhibits dose-dependent cytotoxic effects against ER+ breast cancer cell lines. BC-N102 exhibited time course- and dose-dependent cell cycle arrest via downregulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-Akt, CDK2, and CDK4 while increasing p38 mitogen-activated protein kinase (MAPK), and mineralocorticoid receptor (MR) signaling in breast cancer cell line. In addition, we found that BC-N102 suppressed breast cancer tumorigenesis in vivo and prolonged the survival of animals. Our results suggest that the proper application of BC-N102 may be a beneficial chemotherapeutic strategy for ER+ breast cancer patients.

中文翻译：

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BC-N102 通过干扰细胞周期调节蛋白和激素信号传导以及诱导细胞周期在 G1/G0 期的时程停滞来抑制乳腺癌肿瘤发生

乳腺癌进展和侵袭的机制通常涉及激素信号传导的改变，以及输入细胞周期调节的信号转导途径的上调和/或激活。在此，我们描述了一种合理设计的一流新型小分子抑制剂，用于靶向 ER 阳性乳腺癌的致癌和激素信号传导。BC-N102 治疗对 ER+ 乳腺癌细胞系表现出剂量依赖性细胞毒性作用。BC-N102 通过下调雌激素受体 (ER)、孕激素受体 (PR)、雄激素受体 (AR)、磷脂酰肌醇 3-激酶 (PI3K)、磷酸化 (p)-细胞外蛋白，表现出时程和剂量依赖性细胞周期停滞信号调节激酶 (ERK)、p-Akt、CDK2 和 CDK4，同时增加乳腺癌细胞系中的 p38 丝裂原激活蛋白激酶 (MAPK) 和盐皮质激素受体 (MR) 信号传导。此外，我们发现BC-N102在体内抑制乳腺癌肿瘤发生并延长动物的存活时间。我们的结果表明，正确应用 BC-N102 可能是 ER+ 乳腺癌患者有益的化疗策略。