Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocyto‐kines. Among these, adiponectin has a crucial role in obesity‐associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor‐α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin‐treated MCF‐7 cells, AMPK signaling was not working, resulting in its downstream target acetyl‐CoA carboxylase (ACC) being still active. In contrast, in MDA‐MB‐231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipo‐genesis and cell growth. Upon adiponectin, ERα signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERα‐negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERα‐positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERα‐positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERα‐positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERα‐negative breast cancer, also opportunely combined with antiestrogen therapy..—Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Andò, S. Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer. FASEB J. 32, 4343–4355 (2018). www.fasebj.org