Astrocytes Promote Colonization Of Human Brain With Breast Cancer Cells Via Inhibition Of Kiss1 Expression

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: KISS1 metastatic suppressor is a negative regulator of tumor progression. Recently, we described that breast cancer metastatic cells to the brain exhibit much lower level of KISS1 expression detected by real time PCR and IHC. However little is known about the mechanism that regulates KISS1 in the brain metastatic cells and promotes brain metastases. We hypothesized that loss of KISS1 allows persistence of metastatic cells in the brain. Results: Given the fact that some migrating breast cancer cells possess stem cells (CSC) properties, we stained the primary breast cancer and brain metastatic clinical specimens contain breast cancer cells using CD24, CD44, ESA1 and KISS1 markers. We observed that in the brain metastases, the CSC exhibit low/lack of KISS1 expression, whereas in the MDA-MB-231 model, blood derived circulating cells express comparative to primary xenografts level of KiSS1 expression. Then we co-cultured MDA-231-Br or CN34Br cells with either human microglia (HM) or human astrocytes (HA) to determine the conditions that affect KISS1 expression. We observed that primary human astrocytes downregulate the expression of KISS1, whereas HM conditional media had little effect. Furthermore, we detected that inhibition of KISS1 expression in breast metastatic cells is dependent on the expression of chemokines such CCL2 and CXCL12. This effect was dose dependent and required activation of cellular signaling in the tumor cells. Our data demonstrate that interaction of breast cancer cells with astrocytes inhibits KISS1 metastatic suppressor and contributes to tumorigenesis. Conclusions: Our results provide a new insight into the mechanism that promotes brain metastases, and may have implications for the treatment and prevention of brain metastases. Citation Format: Ilya V. Ulasov, Natalya V. Kaverina, JG Yoon, Hwahyung Lee, Purvaba Sarvaiya, Dmitry Malin, Vincent L. Cryns, Danny R. Welch, Charles K. Cobbs. Astrocytes promote colonization of human brain with breast cancer cells via inhibition of KISS1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-191. doi:10.1158/1538-7445.AM2014-LB-191