Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, 79905, USA.
Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, 97213, USA.
Br J Cancer. 2020 Oct;123(8):1326-1335. doi: 10.1038/s41416-020-0992-6. Epub 2020 Jul 24.
Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied.
The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed.
We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways.
Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells.
孕激素受体膜组份 1（PGRMC1）的表达增加与多种癌症有关，包括乳腺癌。尽管 PGRMC1 是一种调节受体，也是一种潜在的治疗靶点，但它的致癌潜力尚未得到研究。
通过化学抑制和改变 PGRMC1 的表达，研究了 PGRMC1 对乳腺癌生长和进展的影响，并通过使用人类乳腺癌组织的在线基因表达数据集进行了评估。进行了 MTS、流式细胞术、qPCR、Western blotting、共聚焦显微镜和磷酸蛋白质组分析。
我们观察到 ER 阳性 ZR-75-1 和三阴性乳腺癌 MDA-MB-468 细胞中 PGRMC1 的水平均较高。化学抑制和沉默均降低了细胞增殖，诱导细胞周期停滞，促进了细胞凋亡，并降低了 ZR-75-1 和 MDA-MB-468 细胞的迁移和侵袭能力。此外，磷酸蛋白质组分析表明，参与 PI3K/AKT/mTOR 和 EGFR 信号通路的蛋白的激活总体上降低。相比之下，在非恶性 MCF10A 细胞中过表达 PGRMC1 导致细胞增殖增加，并且增强了 PI3K/AKT/mTOR 和 EGFR 信号通路的活性。
我们的数据表明，PGRMC1 通过改变 ER 阳性和三阴性乳腺癌细胞中 PI3K/AKT/mTOR 和 EGFR 信号机制，在调节癌细胞生长中发挥重要作用。
