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

• DOI: 10.1096/fj.201701315r
• Publication Date: 2018-03-07T20:10:05Z
• Authors: Loredana Mauro; Giuseppina Daniel...; Luca Gelsomino; Rocco Malivindi; Leonardo Bruno; Michele Pellegrino; Roberta Tarallo; Domenico Memoli; Alessandro Weisz; Maria Luisa Panno; Sebastiano Andò
• Keywords: 0301 basic medicine; 2. Zero hunger; ERα; LKB1/AMPK signaling; adiponectin levels; breast cancer cells; cell metabolism; Estrogen Receptor alpha; Mice, Nude; Breast Neoplasms; AMP-Activated Protein Kinases; Protein Serine-Threonine Kinases; 3. Good health; Mice; 03 medical and health sciences; AMP-Activated Protein Kinase Kinases; Adipokines; Adipose Tissue; Cell Line, Tumor; Disease Progression; MCF-7 Cells; Animals; Humans; Female; Adiponectin; Cell Proliferation

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. 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 lipogenesis 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.