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metformin may help prevent her2+ breast cancer

Re: metformin may help prevent her2+ breast cancer

Oncotarget. 2011 Dec 24. [Epub ahead of print]
Metformin: Multi-faceted protection against cancer.
Barco SD, Vazquez-Martin A, CufÃ* S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA.
Source
Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia, Spain.
Abstract
The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics.
PMID: 22203527 [PubMed - as supplied by publisher] Free full text

Re: metformin may help prevent her2+ breast cancer

Liked this part also:

Quote:

Metformin and estradiol
Active AMPK inhibits the expression of the aromatase gene in breast adipose tissue by decreasing the local production of estrogen [93]. Furthermore, obese patients with breast cancer exhibit a higher expression of this gene and higher levels of estrogen in breast tissue as a result of increased plasma leptin synthesis, which is caused by obesity. Leptin inhibits AMPK by increasing the expression of aromatase; however, adiponectin activates AMPK. Therefore, metformin-based treatments aimed at activating AMPK and restoring the leptin/adiponectin axis may decrease the occurrence of breast cancer in obese patients.

At this point Metformin appears to simultaneously target mechanisms involved with triple negative, ER+ and Her2+ breast cancer as well as other cancers.

A potent her2 portion of the paper:

Quote:

it is worth mentioning that metformin acts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Herceptin™) to eliminate stem/progenitor cell populations in HER2-gene amplified breast carcinoma cells growing as mammospheres [108]. Moreover, metformin treatment efficiently reverses secondary resistance of HER2-overexpressing cancer cells to the dual HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb™) by suppressing pro-survival pathways (i.e., the anti-apoptotic protein survivin) [109-111].
In HER2-positive tumors, metformin has a dual effect: 1) inhibiting the activity/expression of the HER2 onco-tyrosine kinase and 2) blocking the action of mTOR, a possible mechanism of resistance to trastuzumab [88, 112]. Additionally, by decreasing the levels of circulating insulin and IGF, activation of the IGFR pathway will be avoided. Because transactivation of the IGFR pathway is a well-recognized mechanism underlying de novo (i.e., primary) [113] and acquired (i.e., secondary) [114, 115] resistance to anti-HER2 therapies, metformin’s ability to simultaneously target HER2, while preventing increased IGF-IR signaling may represent a potential therapeutic tool in breast carcinomas resistant to HER2-directed therapy. In support of this, a recently conducted pre-clinical study with trastuzumab-sensitive parental breast cancer cell lines (i.e., BT474 and SKBR3) and trastuzumab-resistant breast cancer sublines (i.e., BT-474-HR20 and SKBR3-pool2) showed that metformin treatment causes significantly more inhibition of proliferation and clonogenicity in trastuzumab-resistant sublines via disruption of HER2/IGF-IR complexes (which are solely present in the resistant sublines) [116]. Importantly, this effect occurred without altering HER2 expression or reduction of IGF-IR expression or activity in the trastuzumab-resistant but not in the sensitive breast cancer cells. The activity of AMPK in cardiac cells is associated with stress-induced survival in response to cytokines or energy depletion. Thus, the concurrent blockage of oncogenic receptors such as HER2, while activating AMPK-related catabolic pathways with metformin would be a highly efficacious therapy to prevent, delay and/or reverse resistance to the HER2 inhibitor while decreasing the risk of cardiomyopathy [109, 117].

Re: metformin may help prevent her2+ breast cancer

This ROCKS - thanks Rich and Lani. wowza ;-)

Kim

Re: metformin may help prevent her2+ breast cancer

Even better are those patients who are determined to help with finding any possible ways to make a difference:

http://her2support.org/vbulletin/showthread.php?t=52216

http://her2support.org/vbulletin/showthread.php?t=52215

http://her2support.org/vbulletin/showthread.php?t=52335

Re: metformin may help prevent her2+ breast cancer

wow! sounds good. Is this still in trials? in use?
sarah

Re: metformin may help prevent her2+ breast cancer

Both. But some non-diabetic cancer patients are getting it "off label" outside of trials.

Re: metformin may help prevent her2+ breast cancer

For those who are interesting in making progress with the possibility of use of metformin for breast cancer:

http://clinicaltrials.gov/ct2/result...tformin+breast

Re: metformin may help prevent her2+ breast cancer

Thanks Rich and Alaska

Re: metformin may help prevent her2+ breast cancer

Yes, many thanks for all of the postings.

Re: metformin may help prevent her2+ breast cancer

I spoke to my oncologist at the recent checkup in November as they do have a Metformin trial on here in Toronto either at Mt. Sinai or Sunnybrook. I printed off the info to take to him as they say to do when you see a trial you are intetrested in. He said I was unable to participate as I am now three years from diagnosis and apparently you have to be one year or less out from surgery, treatment etc. It was the first trial I have seen that I would have qualified for as small tumour, no nodes etc. However I feel so blessed to be three years out and doing well. I hope these trials do show positive outcomes with Metformin. Best wishes to all Lois

Re: metformin may help prevent her2+ breast cancer

Lois,
Would you or your onc or GP consider off label use?

Re: metformin may help prevent her2+ breast cancer

Hi Rich thanks for your response. No I dont think there is any way my family doctor or oncologist would prescribe this. I know on breastcancer.org some women there are getting the prescription from family docs. Take care Lois