Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
BMC Cancer. 2011 Aug 25;11:377. doi: 10.1186/1471-2407-11-377.
Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth.
We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm(3). For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice.
TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands.
Using the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.
流行病学证据表明，循环胰岛素样生长因子-I（IGF-I）水平适度升高与女性乳腺癌风险增加有关。然而，循环 IGF-I 如何促进乳腺癌的发生尚不清楚，但是增加 IGF-I 信号与 ErbB2 阳性乳腺癌中的曲妥珠单抗耐药有关。很少有模型直接研究循环 IGF-I 水平升高对乳腺癌起始和进展的影响。本研究旨在评估循环 IGF-I 独立引发乳腺肿瘤发生和/或加速 ErbB2 介导的乳腺肿瘤生长的能力。
我们将杂合 TTR-IGF-I 小鼠与杂合 MMTV-ErbB2 小鼠杂交，生成 4 种不同基因型：TTR-IGF-I/MMTV-ErbB2（双基因）、TTR-IGF-I 仅、MMTV-ErbB2 仅和野生型（wt）。处女雌性每周两次触诊，并在肿瘤达到 1000mm3 时收获。为了研究正常发育，在 TTR-IGF-I 和 wt 小鼠的 4、6 和 9 周龄时采集血液和组织。
与 ErbB2 和 wt 对照小鼠相比，TTR-IGF-I 和 TTR-IGF-I/ErbB2 双基因小鼠的循环总 IGF-I 中度升高 35%。循环 IGF-I 的升高对青春期乳腺发育没有影响。单独升高 IGF-I 不足以引发乳腺肿瘤发生。升高的循环 IGF-I 对 ErbB2 诱导的乳腺肿瘤发生或转移没有影响，TTR-IGF-I/ErbB2 双基因和 ErbB2 小鼠的肿瘤形成中位时间分别为 30 周和 33 周（p=0.65）。与 ErbB2 相比，来自 ErbB2/TTR-IGF-I 肿瘤的 IGF-I 水平在裂解物中的升高方式相似，但对肿瘤生长速度没有影响（p=0.23）。双基因和 ErbB2 乳腺中的肿瘤类型（实体腺癌）无形态学差异。
使用第一个转基因动物模型将循环 IGF-I 水平升高至与乳腺癌风险增加的女性相当的水平，我们表明，中等水平的全身性 IGF-I 对青春期乳腺发育、乳腺肿瘤起始或促进 ErbB2 驱动的乳腺癌变没有影响。我们的工作表明，ErbB2 诱导的乳腺肿瘤发生与循环 IGF-I 水平的正常变化无关。
