Estrogen receptor alpha interferes with LKBl/AMPK/mTOR signaling activation in adiponectin-treated breast cancer cells

Abstract

Breast cancer is the most common type of tumor and the leading cause of cancer-related deaths in women, worldwide. The cause of breast cancer is multifactorial and includes hormonal, genetic and environmental cues. Obesity is now an accepted risk factor for breast cancer in postmenopausal women, particularly for the hormone-dependent subtype of mammary tumor. Obesity has regarded as a multifactorial disorder characterized by an increased number and size of adipocytes. Adipose tissue is an active metabolic and endocrine organ that secretes many adipocytokines, which act as key mediators in several obesity-associated diseases. Among these, adiponectin represents the most abundant adipose tissue-excreted protein, which exhibits insulin sensitizing, antiinflammatory, and antiatherogenic properties Adiponectin has been proposed as having a key role in the pathogenesis of cardiovascular disease and type 2 diabetes along with obesity-associated malignancies, such as breast cancer. An inverse correlation is reported between obesity and adiponectin, for which low levels of adiponectin represent a risk factor for breast cancer. The role of adiponectin on breast tumorigenesis seems to be dependent on cell phenotypes. Indeed, several in vitro and in vivo studies demonstrated that low adiponectin levels repressed growth in ER-negative breast cancer cells whereas increased proliferation in ER- positive cells. Adiponectin interacts with specific receptors and exerts its effects, including regulation of cell survival, apoptosis and metastasis, via a plethora of signaling pathways. The key molecule of adiponectin action is AMP-activated protein kinase (AMPK), which is mainly activated by liver kinase B1 (LKB1). On the basis of this observations, the aim of the present study was to investigate the effect of adiponectin on LKB1/AMPK signaling in ER-negative (MDA-MB-231) and positive (MCF-7) breast cancer cells. In MCF-7 cells, upon low adiponectin levels, ER impaired LKB1/AMPK interaction by recruiting LKB1 as coactivator at nuclear level, sustaining breast tumor growth. In this condition, AMPK signaling was not working, letting fatty acid synthesis still active. In contrast, in MDA-MB-231 cells the phosphorylated status of AMPK and ACC appeared enhanced, with consequent inhibition of both lipogenesis and cell growth. Thus, in the presence of adiponectin, ERα signaling switched energy balance of breast cancer cells towards a lipogenic phenotype. The same results on tumor growth were reproduced in a xenograft model. These results emphasize how adiponectin action in obese patients is tightly dependent on ERα, addressing that adiponectin may work as growth factor in ERα- positive breast cancer cells.