Abstract P6-04-26: Tamoxifen may block estrogen induced secretion of certain cytokines to interrupt tumor associated macrophage infiltration in breast cancer

Abstract

Abstract The role of tumor microenvironment during the initiation and progression of breast cancer is now realized to be of critical importance, both for understanding of the fundamental cancer biology and exploiting relatively new mechanism for breast cancer metastasis. Macrophage is a one of the most common components in the breast cancer microenvironment. Normally, the macrophage in tumor microenvironment is referred to tumor associated macrophage (TAM), which shares some attributes of alternatively activated macrophage. Many pre-clinical and clinical studies demonstrate an inverse correlation between TAM infiltration and patients' prognosis indicating a macrophage supporting role for tumor progression. It is well documented that selective patients with breast cancer can benefit from anti-estrogen therapy. However, the mechanisms involved are still not fully elucidated. Our previous study indicates that highly tumorigenic breast cancer cell line MDA-MB-231 can educate monocyte differentiation into alternatively activated macrophage, while weakly tumorigenic cell line MCF-7 (without estrogen supplementation) can not. In the present study, we explored the effects of estrogen and tamoxifen on the secreting of certain cytokines, which are required for monocyte chemotaxis and differentiation. Breast cancer cell lines with different estrogen receptor status were applied to estimate the level of cytokines (IL4, IL6, M-CSF, GM-CSF, and MCP-1) before and after cultured with 17β-estradiol, tamoxifen or both. We found that weakly invasive breast cancer cell lines (MCF-7, T47D, MDA-MB-468, and SKBR3) generally expressed lower levels of such cytokines compared with highly invasive breast cancer cell lines (MDA-MB-231, MDA-MB-231-BO, MDA-MB-231 HM, Bcap 37, BT549, and Hs578T) at baseline. However, the discrepancies could be compensated partially by exposure to 10nM 17β-estradiol in estrogen receptor (ER) positive cell lines (MCF-7 and T47D). Moreover, the compensation was substantially blocked by 2μM tamoxifen. On the contrary, tamoxifen, alone, didn't affect the secretion of such cytokines mentioned above in vitro. Based on these findings, we tentatively concluded that some patients with ER positive breast cancers benefiting from anti-estrogen therapy may partially attributes to blocking monocyte differentiation into TAM, which destroyed the tumor microenvironment. These findings suggest the future possibility of using TAM as a novel therapeutic target in patients with anti-estrogen resistance and primary triple-negative breast cancers (TNBC) with no effectively therapeutic measures nowadays, which are defined by lack of estrogen receptor, progesterone receptor and ERBB2 gene amplification, representing approximately 16% of all breast cancers. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-26.