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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 antidiabetes AMPK-activating 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.

SUBMITTER: Hampsch RA 

PROVIDER: S-EPMC7367755 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

AMPK Activation by Metformin Promotes Survival of Dormant ER<sup>+</sup> Breast Cancer Cells.

Hampsch Riley A RA   Wells Jason D JD   Traphagen Nicole A NA   McCleery Charlotte F CF   Fields Jennifer L JL   Shee Kevin K   Dillon Lloye M LM   Pooler Darcy B DB   Lewis Lionel D LD   Demidenko Eugene E   Huang Yina H YH   Marotti Jonathan D JD   Goen Abigail E AE   Kinlaw William B WB   Miller Todd W TW  

Clinical cancer research : an official journal of the American Association for Cancer Research 20200422 14


<h4>Purpose</h4>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.<h4>Experimental design</h4>Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER<su  ...[more]

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