Ghatge Radhika P, Jacobsen Britta M, Schittone Stephanie A, Horwitz Kathryn B
University of Colorado Health Sciences Center, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, Denver, Colorado, USA.
Breast Cancer Res. 2005;7(6):R1036-50. doi: 10.1186/bcr1340. Epub 2005 Nov 2.
Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells.
A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor.
In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous.
Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor.
醋酸甲羟孕酮（MPA）是用于口服避孕和激素替代疗法的主要孕激素，它被认为会增加乳腺癌风险。这种风险是由于其孕激素特性还是雄激素特性呢？为了解决这个问题，我们评估了MPA与孕酮和双氢睾酮（DHT）相比在人乳腺癌细胞中的转录效应。
构建并鉴定了一种新的孕激素受体阴性、雄激素受体阳性的人乳腺癌细胞系，命名为Y-AR。使用合成启动子/报告基因构建体进行转录测定，并在缺乏或含有孕激素受体和/或雄激素受体的细胞中比较孕酮、MPA和DHT的内源性基因表达谱。
在孕激素受体阳性细胞中，在瞬时转录测定中发现MPA通过两种孕激素受体亚型都是一种有效的孕激素。有趣的是，DHT通过B型孕激素受体发出信号。比较孕酮和MPA的内源性孕激素受体调节基因的表达谱表明，尽管MPA可能比孕酮稍微更有效，但在性质上与孕酮相似。为了研究MPA通过雄激素受体的作用，使用Y-AR细胞比较孕酮、MPA和DHT进行表达谱分析。这些研究表明，DHT和MPA通过雄激素受体存在广泛的基因调控重叠，而与孕酮没有。有趣的是，药理剂量的MPA和生理剂量的MPA之间没有差异，这表明高剂量治疗性MPA可能是多余的。
我们对MPA和孕酮基因调控谱的比较表明，对于生理性激素替代疗法，MPA的作用并不单独模仿内源性孕酮的作用。临床上，MPA复杂的药理学不仅影响其副作用谱；而且MPA增加的乳腺癌风险和/或其在癌症治疗中的疗效可能部分是由雄激素受体介导的。
