Massarweh Suleiman, Osborne C Kent, Creighton Chad J, Qin Lanfang, Tsimelzon Anna, Huang Shixia, Weiss Heidi, Rimawi Mothaffar, Schiff Rachel
Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Cancer Res. 2008 Feb 1;68(3):826-33. doi: 10.1158/0008-5472.CAN-07-2707.
Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)-positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2.
并非所有乳腺癌都对他莫昔芬有反应，而且许多乳腺癌尽管最初有疗效，但仍会产生耐药性。我们使用雌激素受体（ER）阳性乳腺癌的体内模型（MCF-7异种移植瘤）来研究这种耐药性的机制，并制定规避耐药性的策略。在对照雌激素处理的肿瘤中几乎检测不到的表皮生长因子受体（EGFR）和HER2，在使用他莫昔芬时略有增加，而在肿瘤产生耐药性时则显著增加。抑制EGFR/HER2的吉非替尼可增强他莫昔芬的抗肿瘤作用并延缓获得性耐药，但对雌激素刺激的生长没有影响。在他莫昔芬耐药的肿瘤中，p42/44和p38丝裂原活化蛋白激酶（均为EGFR/HER2的下游分子）的磷酸化水平升高，并被吉非替尼抑制。耐药肿瘤中磷酸化的AKT（也是EGFR/HER2的下游分子）没有明显增加，但仍被吉非替尼抑制。与敏感组相比，在他莫昔芬耐药的肿瘤中，可与EGFR和膜ER相互作用的磷酸化胰岛素样生长因子-IR（IGF-IR）升高。然而，即使在获得性耐药时，包括总IGF-IR本身和孕激素受体在内的ER调节基因产物仍受到抑制。他莫昔芬对经典ER基因组功能的拮抗作用在这些耐药肿瘤中甚至在过表达HER2（MCF-7 HER2/18）且对他莫昔芬原发耐药的肿瘤中仍然存在。总之，尽管他莫昔芬持续抑制ER基因组功能，但EGFR/HER2可能介导ER阳性乳腺癌中的他莫昔芬耐药。IGF-IR的表达仍然依赖于ER，但在他莫昔芬耐药的肿瘤中被激活。这项研究为在临床研究中将HER抑制剂与他莫昔芬联合使用提供了理论依据，即使在最初未过表达EGFR/HER2的肿瘤中也是如此。
