白介素1β与白介素6双重抑制显著阻止乳腺癌发生的基础研究

IL1β and IL6 are two cytokines that play important roles in response to inflammation and infection. IL1β and IL6 are expressed at very low level in normal human breast epithelial cells. However, the expression of IL1β and IL6 is significantly increased in breast cancer. In preliminary studies, we found that deletion of IL6 significantly delayed breast cancer development, while deletion of IL1β did not significantly delay breast cancer development in mouse models. Surprisingly, deletion of both IL1β and IL6 completely blocked breast cancer development in MMTV-c-Neu transgenic mammary tumor mouse models, suggesting that IL1β and IL6 dual inhibition would be a very efficient way for the treatment and prevention of breast cancer. Importantly, mice with deletion of both IL1β and IL6 are viable and largely normal. Thus, inhibition of IL1β and IL6 will be not only very powerful but also very safe for the prevention and treatment of breast cancer. We will (1) investigate whether IL1β and IL6 dual inhibition blocks or very significantly suppresses oncogene-driven breast tumorigenesis; (2) investigate whether IL1β or/and IL6 from mammary (tumor) epithelial cells or from stromal/immune cells are required for oncogene-driven breast tumorigenesis; and (3) investigate whether IL1β and IL6 dual inhibition impairs breast tumorigenesis by targeting breast cancer stem cells. We submit that these studies will provide the foundation for the development of novel and efficient therapeutic strategies for the treatment and/or prevention of breast cancer. .

IL1β和IL6与肿瘤关系密切，但其具体作用及机制尚不清楚。我们在癌基因Neu诱发小鼠乳腺癌模型的前期研究中发现，IL6敲除能部分抑制乳腺癌的发生，而IL1β敲除对乳腺癌发生则无明显抑制，有趣的是，IL6/IL1β双敲除能彻底抑制小鼠乳腺癌的发生。另外，IL6/IL1β双敲除小鼠发育及寿命均无明显异常。据此，我们提出：IL6/IL1β双重抑制能安全有效地防治乳腺癌。为此，项目拟进一步利用基因敲除及转基因小鼠模型检测IL1β/IL6双重抑制是否彻底或显著阻止乳腺癌的发生，运用乳腺上皮细胞移植技术探讨乳腺上皮细胞源性与非乳腺上皮细胞源性IL1β和IL6在乳腺癌发生中的作用。采用基因干扰、 移植瘤模型等技术探讨IL1β与IL6是否通过调节肿瘤干細胞而促进乳腺癌的发生。项目研究结果将揭示乳腺癌发生的新机制，为乳腺癌的治疗和预防提供新的靶标和安全有效的方案。

IL1β和IL6与肿瘤关系密切，但其具体作用及机制尚不清楚。我们发现：在癌基因Neu诱发小鼠乳腺癌模型中，IL6敲除能部分抑制乳腺癌的发生，IL1β敲除对乳腺癌发生则无明显抑制，而IL6/IL1β双敲除能彻底抑制小鼠乳腺癌的发生。同样，在癌基因PyMT诱发小鼠乳腺癌模型中，IL6敲除能部分抑制乳腺癌的发生，IL1β敲除对乳腺癌发生抑制作用，IL6/IL1β双敲除显著抑制小鼠乳腺癌的发生。进一步研究发现上皮细胞和淋巴细胞中IL1β/IL6双重抑制能显著减慢乳腺癌的发生。有趣的是，IL6敲除乳腺癌转基因小鼠尽管乳腺癌发生晚，但一旦发生其恶性极高，这可能与细胞干性有关。而IL6敲除细胞内IL1β表达增高与细胞干性增强相联系。本研究揭示了乳腺癌发生的新机制，为乳腺癌的治疗和预防提供新的靶标。IL6/IL1β双敲除小鼠发育及寿命均无明显异常，说明IL6/IL1β双重抑制能安全有效地防治乳腺癌。