AMPK Activation by Metformin Promotes Survival of Dormant ER+ Breast Cancer Cells

Abstract

Purpose: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. Experimental Design: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy. Results: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPKactivating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.Conclusions: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.

Carnitine palmitoyl transferase 1A is a novel diagnostic and predictive biomarker for breast cancer

“…According to previous studies, CPT1A amplification was found in 20% of ER-positive breast cancer cases, and the CPT1A protein level is elevated in most breast cancer cell lines [ 41 ]. CPT1A is regulated by c-MYC or AMPK in breast cancer, and promotes breast cancer metastasis or therapeutic resistance through several oncogenic signaling pathways, such as VEGF, ERK and Src pathways [ 25 – 27 , 29 , 42 ].…”

Cytotoxicity of metformin against HT29 colon cancer cells contributes to mitochondrial Sirt3 upregulation

“…[ 17 ] Previous studies have shown that metformin can exert antineoplastic effects by recruiting the kinase enzyme activated by adenosine monophosphate (AMPK) and reducing the phosphorylation of protein kinase B, mammalian target of rapamycin (mTOR), and p70S6k in different types of tumors. [ 18,19 ] In addition, metformin regulates apoptosis signaling [ 20 ] by inhibiting phosphorylation of BAD and Bcl‐2, procaspase 9, procaspase 3, and procaspase 7, and upregulation of BAD, cytochrome c, and Apaf‐1 protein. [ 21,22 ] However, metformin is capable of affecting the mitochondrial function.…”

New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

“…Controversially, metformin may have the negative effect of accelerating cancer development. The recent in vitro and in vivo results of the study by Hampsch et al suggested that metformin may promote the survival of dormant estrogen receptor (ER)-positive breast cancer cells by activating AMPK in a context-dependent manner [143]. Therefore, despite recent evidence supporting the anticancer and chemopreventive effects of metformin, the context-dependent effects of AMPK in cancer must be considered in the future when administering metformin as a chemoprevention or adjuvant treatment [144].…”