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

Abstract

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.

Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression

“…Moreover, pretreatment of MDA‐MB‐231 breast cancer cells with adiponectin or its intra‐tumoural or systemic administration reduced mammary tumour growth in xenograft models, through the involvement of PI3K/Akt/and GSK‐β‐catenin signalling . In agreement with these findings, our recent data demonstrated a marked reduction of tumour size in adiponectin‐pretreated MDA‐MB‐231 cells implanted in nude mice, as also evidenced by a decreased expression of tumour cell mitotic index Ki67, concomitant with an enhanced activation of AMPK signalling . Besides, in another murine mammary tumour model, administration of adiponectin into tumour mass stimulated PP2A activity through AMPK, inhibiting cell growth and invasiveness .…”

“…Indeed, immunofluorescence analysis and proximity ligation assay, in cells treated with adiponectin, revealed that LKB1 localized in both nucleus and cytoplasm in MCF‐7 cells, while in MDA‐MB‐231 cells, it was mostly detectable in the cytoplasm. The nuclear localization of LKB1/ERα highlights the well‐documented role of LKB1 as ERα coactivator (Figure B). These findings were further supported by the observation that adiponectin exposure induced the recruitment of LKB1 on a classic ER element sequence located in the promoter region of estrogen‐dependent genes .…”

“…More recently, it has been demonstrated, in ERα‐positive breast cancer cells, that LKB1 binds to ERα and in doing so makes its cytosolic pool not adequate to activate AMPK signalling, thus maintaining mTOR signalling and sustaining cell growth (Figure B). In contrast, in ERα‐negative breast cancer cells, the interaction of LKB1 with AMPK resulted in mTOR inhibition, which negatively regulates breast cancer cell proliferation (Figure B). Indeed, immunofluorescence analysis and proximity ligation assay, in cells treated with adiponectin, revealed that LKB1 localized in both nucleus and cytoplasm in MCF‐7 cells, while in MDA‐MB‐231 cells, it was mostly detectable in the cytoplasm.…”

“…Moreover, TGFBR1 , IGFBP3 , and MAGED1 , which modulate membrane signalling converging in cell cycle inhibition, were up‐regulated along with other genes acting as a tumour suppressor, such as PML , and RASSF5. In addition, genes controlling apoptosis and cell death as FAS , BIK , BID , and caspases were significantly increased …”

“…Specifically, some authors have evidenced significant anti‐proliferative effects in ERα‐positive breast cancer cells, while others did not notice substantial change in MCF‐7 cell growth, upon adiponectin exposure . More recent studies have also demonstrated a stimulatory effect of this adipokine on MCF‐7 cell proliferation …”