Abstract 4968: Importance of tumor microenvironment in the preclinical estrogen receptor positive breast cancer- Primary tumor and bone metastasis models

Estrogen receptor positive (ER+) breast cancer has ability to metastasize to bone in high frequency. Bone is known to be fertile soil for metastasized cancer cells to survive and in turn, metastasized tumor cells alter normally balanced bone environment. Prevention and treatment of bone metastasis is challenging and better understanding why bone metastasis are resistant to current therapies is needed. Aim of the present study was to explore the role of tumor microenvironment and estrogen supplementation on growth of primary breast cancer tumor and bone metastasis to establish predictive ER+ breast cancer models for drug development. ER+ human breast cancer MCF-7 cells were inoculated into mammary fat pad and in the tibia of female athymic nude mice. Mice received either hormonal supplementation (17-beta estradiol pellet, E2) or placebo. Tumor growth was followed for 5 and 9 weeks. From one group, E2 supplementation was removed on study week 5 and tumor growth was followed for 4 weeks. During the study, blood samples were collected for serum steroid concentration measurements and at the end, histopathological evaluation and immunohistochemical (IHC) stainings were performed to examine tumor steroid hormone receptor expression. Orthotopic MCF-7 tumor growth was clearly hormone dependent. E2 supplementation, that increased serum estradiol for app. 3-fold, supported tumor growth and when E2 was removed, tumor size decreased and no tumor growth was observed thereafter. In the full absence of E2 supplement, no orthotopic tumor growth was observed. In contrast, when MCF-7 cells were inoculated into tibia, tumor growth was observed both with and without E2 supplement. IHC stainings confirmed orthotopic tumor to express ER, PR and AR when animals received E2. After E2 removal, orthotopic tumors expressed still ER and AR but no longer PR. Also intratibial tumors expressed ER and PR in the presence of E2, but no PR in the absence of E2 supplement. E2 is needed to support MCF-7 tumor growth when cancer cells are inoculated orthotopically into mammary fat pad. No orthotopic tumor growth is observed in the absence of E2 supplement. In contrast, in the bone microenvironment, MCF-7 cells form tumor even in the absence of E2 supplement. Results highlight importance of tumor microenvironment in the breast cancer progression and also refer why tumor in the different sites may be resistant to therapy. Taking together, when developing new therapies against breast cancer, focus should be addressed not only on primary tumor growth but also on bone metastasis where cancer cells are under influence of bone environment. Citation Format: Jenni Bernoulli, Mari I. Suominen, Tiina Kahkonen, Jenni Maki-Jouppila, Jussi M. Halleen, Riikka Oksala. Importance of tumor microenvironment in the preclinical estrogen receptor positive breast cancer- Primary tumor and bone metastasis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4968. doi:10.1158/1538-7445.AM2017-4968