Medroxyprogesterone acetate (MPA) is a first generation progestin that has been in clinical use for various hormonal conditions in women since the 1960s. Although developed as a progesterone receptor (PR) agonist, MPA also has strong binding affinity for other steroid receptors. This promiscuity confounds the mechanistic action of MPA in target cells that express multiple steroid receptors. This study is the first to assess the relative contribution of progesterone, androgen and glucocorticoid receptors in mediating the transcriptional activity of MPA on endogenous targets in breast cancer cells that endogenously express all three receptors at comparable levels. Gene expression profiling in estrogen receptor positive (ER+) ZR-75-1 breast cancer cells demonstrated that although the MPA-regulated transcriptome strongly overlapped with that of Progesterone (PROG), 5α-dihydrotestosterone (DHT) and Dexamethasone (DEX), it clustered most strongly with that of PROG, suggesting that MPA predominantly acts via the progesterone receptor (PR) rather than androgen receptor (AR) or glucocorticoid receptor (GR). Subsequent experiments manipulating levels of these receptors, either through specific culture conditions or with lentiviral shRNAs targeting individual receptors, also revealed a stronger contribution of PR compared to AR and GR on the expression of endogenous target genes that are either commonly regulated by all ligands or specifically regulated only by MPA. A predominant contribution of PR to MPA action in ER+ T-47D breast cancer cells was also observed, although a stronger role for AR was evident in T-47D compared to that observed in ZR-75-1 cells. Network analysis of ligand-specific and commonly regulated genes demonstrated that MPA utilises different transcription factors and signalling pathways to inhibit proliferation compared with PROG. This study reaffirms the importance of PR in mediating MPA action in an endogenous breast cancer context where multiple steroid receptors are co-expressed and has potential implications for PR-targeting therapeutic strategies in ER+ breast cancer.

中文翻译：

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乙酸甲羟孕酮在雌激素受体阳性乳腺癌细胞中的抗增殖转录作用主要由黄体酮受体介导。

醋酸甲羟孕酮（MPA）是第一代孕激素，自1960年代以来已在临床上用于女性的各种激素状况。尽管已发展为孕激素受体（PR）激动剂，但MPA对其他类固醇受体也具有很强的结合亲和力。这种混杂混淆了MPA在表达多种类固醇受体的靶细胞中的机械作用。这项研究是第一个评估黄体酮，雄激素和糖皮质激素受体在介导MPA对内源性靶标的乳腺癌细胞中的MPA转录活性方面的相对贡献的方法，内源性靶标以可比较的水平内源性表达所有这三种受体。雌激素受体阳性（ER +）ZR-75-1乳腺癌细胞的基因表达谱显示，尽管MPA调节的转录组与孕酮（PROG），5α-二氢睾丸激素（DHT）和地塞米松（DEX）强烈重叠，与PROG最为相似，表明MPA主要通过孕激素受体（PR）而不是雄激素受体（AR）或糖皮质激素受体（GR）起作用。随后的实验，通过特定的培养条件或靶向单个受体的慢病毒shRNA操纵这些受体的水平，与AR和GR相比，PR对内源靶基因表达的贡献也要强于AR和GR，内源靶基因通常受所有配体调控或特异性调控仅受MPA监管。还观察到PR对ER + T-47D乳腺癌细胞中MPA作用的主要贡献，尽管与ZR-75-1细胞相比，T-47D中AR的作用更为明显。对配体特异性和共同调控基因的网络分析表明，与PROG相比，MPA利用不同的转录因子和信号传导途径抑制增殖。这项研究重申了PR在介导多种类固醇受体共生的内源性乳腺癌环境中介导MPA作用中的重要性，并且对ER +乳腺癌中PR靶向治疗策略具有潜在意义。对配体特异性和共同调控基因的网络分析表明，与PROG相比，MPA利用不同的转录因子和信号传导途径抑制增殖。这项研究重申了PR在介导多种类固醇受体共生的内源性乳腺癌环境中介导MPA作用中的重要性，并且对ER +乳腺癌中PR靶向治疗策略具有潜在意义。对配体特异性和共同调控基因的网络分析表明，与PROG相比，MPA利用不同的转录因子和信号传导途径抑制增殖。这项研究重申了PR在介导多种类固醇受体共生的内源性乳腺癌环境中介导MPA作用中的重要性，并且对ER +乳腺癌中PR靶向治疗策略具有潜在意义。