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Background: EphA4 (the erythropoietin-producing hepatocellular receptor A4) belongs to a large family of receptor tyrosine kinases that play critical roles in cancer progression. We have previously reported that the absence of EphA4 expression decreases the amount of IGF1 in the circulation and locally in tissues, which contributes to the short stature (Cell Reports 2012). It is known that 4T1 murine breast cancer is a good model of human metastatic breast cancer. 4T1 cells are also known to produce a large amount of granulocyte colony-stimulating factor which can cause extramedullary hematopoiesis associated with a poor recipient prognosis. Aim: To investigate whether EphA4-deleted microenvironment affects growth of primary tumors, tumor metastasis, and extramedullary hematopoiesis via a novel EphA4-mediated IGF1 synthesis pathway. Methods: We isografted 105 mouse breast cancer cells (4T1) into the left inguinal mammary fatpad of both EphA4-knockout (KO) and control wild type (WT) female littermate mice. The parameters evaluated in vivo were growth of the primary tumors, distribution of metastatic foci, number of peripheral blood leukocytes (PBL), and splenomegaly. To examine the effect of IGF1 treatment on these parameters, recombinant human IGF1 (5 mg/kg body weight (BW)/day) was subcutaneously injected into the EphA4-KO mice for 9 weeks starting 4 weeks before grafting 4T1 cells. And the corresponding WT control mice were treated with saline alone for the same period. We evaluated the extent of metastasis by counting the number of metastatic foci larger than 1 mm in diameter in the lung, heart, liver, kidney, adrenal glands, lymph nodes, peritoneum, pleura and ovary. Results: In the absence of IGF1 injection, both the weight of primary tumors and the number of metastatic tumor foci were significantly reduced in EphA4-KO mice as compared with those in control WT littermate mice (n=6 of each genotype, t-test P Conclusions: EphA4 expression in the tumor microenvironment plays an important role in tumor growth, metastasis, leukemoid reaction and splenomegaly. Deletion of EphA4 in the microenvironment delays primary tumor growth and metastasis and reduces leukemoid reaction mainly by regulating the amount of IGF1 in the circulation and tissues. However, splenomegaly might not solely be mediated by an IGF1 signal. Our findings may prove a new therapeutic target for breast cancer. Citation Format: Xuefeng Jing, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Kenryo Furushima, Daiki Arai, Kazuki Kawakami, Kazushige Sakaguchi. EphA4-deleted microenvironment regulates cancer development of isografted 4T1 murine breast cancer cells via reduction of an IGF1 signal [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-08.