A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis.
A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis.
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DOI：
10.1186/1471-2407-11-377
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发表时间：
2011-08-25
期刊：
影响因子：
3.8
通讯作者：
Lee AV
中科院分区：
文献类型：
--
作者：
Dearth RK;Kuiatse I;Wang YF;Liao L;Hilsenbeck SG;Brown PH;Xu J;Lee AV
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。循环IGF-I如何促进乳腺癌发病率尚不清楚，然而，在ErbB2阳性乳腺癌中，IGF-I信号的增加与曲妥珠单抗耐药有关。很少有模型直接研究了中度高水平的循环igf - 1对乳腺癌发生和发展的影响。本研究的目的是评估循环igf - 1独立启动乳腺肿瘤发生和/或加速ErbB2介导的乳腺肿瘤生长进展的能力。我们将杂合子TTR-IGF-I小鼠与杂合子MMTV-ErbB2小鼠杂交，产生4种不同的基因型：TTR-IGF-I/MMTV-ErbB2（双基因）、TTR-IGF-I、MMTV-ErbB2和野生型（wt）。处女雌性每周触诊两次，当肿瘤达到1000 mm3时切除。为了研究trr - igf - i和wt小鼠的正常发育，分别在4、6和9周龄采集血液和组织。与ErbB2和wt对照小鼠相比，TTR-IGF-I和TTR-IGF-I/ErbB2基因小鼠的循环总IGF-I增加了35%。升高循环igf - 1对青春期乳腺发育无影响。单纯通过转基因增加igf - 1并不足以引发乳腺肿瘤的发生。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，trr -IGF-I/ErbB2基因小鼠和ErbB2小鼠的中位肿瘤形成时间分别为30周和33周（p = 0.65）。与ErbB2相比，ErbB2/ trr -IGF-I肿瘤裂解物中IGF-I的水平以与循环IGF-I相似的方式升高，然而，对肿瘤生长速率没有影响（p = 0.23）。双基因型和ErbB2型乳腺在肿瘤类型（实体腺癌）上没有形态学差异。利用第一个转基因动物模型，将循环中的IGF-I水平提高到与乳腺癌风险增加的女性相当的水平，我们发现中度高水平的全身IGF-I对青春期乳腺发育、启动乳腺肿瘤发生或促进ErbB2驱动的乳腺癌发生没有影响。我们的研究表明，erbb2诱导的乳腺肿瘤发生与IGF-I循环水平的正常变化无关。
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 mm3. 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.
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