Inhibition of the PI3K-AKT-mTOR pathway suppresses the adipocyte-mediated proliferation and migration of breast cancer cells

Jae-Yeo Park; Shi-Eun Kang; Kwang Seok Ahn; Jae-Young Um; Woong Mo Yang; Miyong Yun; Seok-Geun Lee

doi:10.7150/jca.37975

Inhibition of the PI3K-AKT-mTOR pathway suppresses the adipocyte-mediated proliferation and migration of breast cancer cells

J Cancer. 2020 Feb 10;11(9):2552-2559. doi: 10.7150/jca.37975. eCollection 2020.

Authors

Jae-Yeo Park¹, Shi-Eun Kang¹, Kwang Seok Ahn^{1

2}, Jae-Young Um¹, Woong Mo Yang¹, Miyong Yun^{1

3

4}, Seok-Geun Lee^{1

2

5}

Affiliations

¹ Department of Science in Korean Medicine and Comorbidity Research Institute, Kyung Hee University, Seoul, Republic of Korea.
² KHU-KIST department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
³ Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University, Seoul, Republic of Korea.
⁴ Sejong Arctic Research Center, Sejong University, Seoul, Republic of Korea.
⁵ Bionanocomposite Research Center, Kyung Hee University, Seoul, Republic of Korea.

Abstract

Objective: Although it is well known that adipocyte significantly affects breast cancer progression, its mechanism has not been fully understood. Here, we analyzed the effect of adipocytes on breast cancer progression including cell proliferation and migration. Materials and Methods: We treated the conditioned media obtained from mouse 3T3-L1-derived or human adipose tissue-derived mesenchymal stem cells (hAMSC)-derived adipocytes to breast cancer cells, MCF-7 and MDA-MB-231. And then, cells viability and proliferation were analyzed using MTT assays and colony forming assays, respectively. Also mRNA expression of inflammatory cytokines and proteins expression in main signal pathway were analyzed by RT-qPCR and immunoblotting, respectively. Results: Adipocyte-derived conditioned media increased the proliferation and migration of MCF-7 and MDA-MB-231 cells while little effects in a human normal immortalized mammary epithelial cell line MCF10A. In addition, adipocyte-derived conditioned media induced phosphorylation of AKT and mTOR and upregulated the expression of target genes of the PI3K-AKT-mTOR pathway including IL6, IL1β, IL1α and TNFα in breast cancer cells. Furthermore, BEZ235 a dual inhibitor of PI3K and mTOR significantly decreased the adipocyte-mediated the proliferation and migration of breast cancer cells. Conclusion: Adipocyte-derived conditioned media enhance the proliferation and migration of breast cancer cells through the PI3K-AKT-mTOR pathway, supporting the importance of heterotypic interactions between breast cancer cells and adipocytes in the tumor microenvironment.