Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Cancer Cell. 2011 Jul 12;20(1):119-31. doi: 10.1016/j.ccr.2011.05.026.
Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%-30% of cases that are ER negative (ER-). Androgen receptor (AR) is expressed in 60%-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER- breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER-/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER-/HER2+ breast cancers.
针对雌激素受体 (ER) 的乳腺癌内分泌疗法在 25%-30% 的 ER 阴性 (ER-) 病例中无效。雄激素受体 (AR) 在 60%-70% 的乳腺癌肿瘤中表达，与 ER 状态无关。雄激素和 AR 如何调节乳腺癌的生长在很大程度上仍然未知。我们发现 AR 在过表达 HER2 的 ER-乳腺癌中富集。通过分析 AR 顺式作用元件和 ER-/HER2+乳腺癌中雄激素调节的基因表达，我们发现 AR 通过 WNT7B 和 HER3 的直接转录诱导，介导配体依赖性的 Wnt 和 HER2 信号通路的激活。AR、Wnt 或 HER2 信号的特异性靶向抑制了雄激素刺激的肿瘤细胞生长，这为 ER-/HER2+乳腺癌提供了潜在的治疗方法。
