Estrogen enhances tumor growth and angiogenesis indirectly via mediation of bone marrow­derived cells as well as directly through stimulation of tumor and endothelial cells.

Estradiol (E2) is a prime culprit for enhancing the progression of female hormone­related cancers. Bone marrow­derived cells (BMDCs) have been found to play a pivotal role in tumor growth. Estrogen receptors (ERs) are also found on certain subtypes of BMDCs, in addition to endothelial cells (ECs) and certain tumor cells. However, the role of BMDCs in E2­induced tumor biology is still unclear. Thus, the effects of E2 on ER­negative 4T1 breast cancer growth, the mobilization and recruitment of BMDCs, and interactions among BMDCs, ECs, and 4T1 cells were investigated. The results showed that E2 potentiated 4T1 tumor growth and angiogenesis in mice subjected to sham operation, ovariectomy (OVX), or OVX and E2 replacement treatment. E2 supplementation in mice with OVX upregulated the transcription of stromal cell­derived factor­1 (SDF­1) mRNA in tumor tissues and enhanced the recruitment of BMDCs into tumor tissues in vivo. E2 deficiency significantly decreased proangiogenic CXCR4+, ß3+, Sca­1+ and CXCR4+ß3+ BMDCs circulating in the peripheral blood. Cell­based system analyses showed that E2 augmented the transcription of ß3 mRNA in ECs, increased the adhesion of BMDCs to ECs. In addition, E2 enhanced the BMDC­induced EC proliferation and migration, the BMDC­induced 4T1 proliferation and the 4T1­stimulated EC proliferation in addition to enhancing the proliferation of tumor cells and the migration of ECs in vitro. Therefore, E2 enhanced the growth of breast tumors by stimulating tumor cells and ECs directly, as well as by increasing proangiogenic BMDC mobilization and recruitment leading to augmentation of the tumor and EC functions indirectly by cell proliferation assay. These findings reveal a separate mechanism via which E2 promotes the growth of female hormone­dependent tumors, which may be useful in explorations of new therapies for related cancers.