Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2012) 29 S7.1

ICEECE2012 Symposia Hormones, metabolism and cancer: more than coincidences? (3 abstracts)

An epigenetic switch linking inflammation to cancer and the use of metformin as an anti-cancer drug

K. Struhl


Harvard Medical School, Boston, Massachusetts, USA.


Transient activation of Src oncoprotein can mediate an epigenetic switch from immortalized breast cells to a stably transformed line that forms self-renewing mammospheres that contain cancer stem cells (CSCs). Src activation triggers an inflammatory response mediated by NF-kB that directly activates Lin28 transcription and rapidly reduces the level of let-7 microRNAs. Let-7 inhibits IL6 expression, and IL6 activates STAT3. Importantly, IL6 activates NF-kB, thereby completing a positive feedback loop. Furthermore, STAT3 activates transcription of the miR-21 and miR-181b microRNAs, and each of these is sufficient to activate the epigenetic switch. This positive feedback loop is enhanced in CSCs as compared to non-stem cancer cells in the same population. Thus, inflammation activates a positive feedback loop that involves NF-kB, Lin28, Let-7, IL6, STAT3, miR-21, and miR-181b that maintains the epigenetic transformed state for many generations in the absence of the inducing signal.

The cancer stem cell (CSC) hypothesis suggests that, unlike most cells within a tumor, CSCs resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Relatively low doses of metformin, a standard diabetes drug, inhibits transformation and selectively kills breast CSCs. The combination of metformin and doxorubicin kills both CSCs and non-stem cancer cells in culture, and it prevents relapse much more effectively than either drug alone in mouse xenografts. Metformin is equally effective combined with other chemotherapeutic agents, and with a 4-fold reduced dose of doxorubicin. The combination of metformin and doxorubicin prevents relapse in xenografts involving cancer cell lines from several, but not all, developmental lineages. Metformin appears to inhibit the inflammatory pathway. These results support the CSC hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.

Volume 29

15th International & 14th European Congress of Endocrinology

European Society of Endocrinology 

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