metformin (common anti diabetes drug) decreases her2 protein levels by 85%

[Lani]

Cell Cycle. 2009 Jan 1;8(1). [Epub ahead of print]

The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells.

Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA.
Catalan Institute of Oncology (ICO)-Health Services Division of Catalonia, and Girona Biomedical Research Institute (IdIBGi), Dr. Josep Trueta University Hospital of Girona, Girona, Catalonia, Spain.
Population studies have revealed that treatment with the antidiabetic drug metformin significantly associates with reduced breast cancer risk. Animal studies have shown that metformin suppresses the development of mammary carcinomas in transgenic female mice carrying a HER2 oncogene, but not that of spontaneous tumors. We herein demonstrate that HER2 oncoprotein itself may represent a key cellular target involved in the anti-breast cancer actions of metformin. First, ectopical overexpression of HER2 oncogene significantly enhances metformin-induced breast cancer cell growth inhibition. Second, metformin treatment drastically downregulates HER2 protein levels (up to 85% reduction) in a dose- and time-dependent manner. Metformininduced inhibition of HER2 take places regardless the molecular mechanism contributing to HER2 overexpression (i.e., human HER2 cDNA exogenously driven by a viral promoter and naturally occurring endogenous HER2 gene amplification). Mechanistically, metformin-induced suppression of HER2 overexpression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity. Compound C- and small interference RNA (siRNA)-induced blockade of AMPK activity/expression fail to prevent the anti-HER2 effect of metformin while AMPK hyperactivation following exposure to the AMP analog AICAR is not sufficient to downregulate HER2 expression. HER2-positive breast cancer cells transfected with p70S6K1 siRNA become completely refractory to metformin-induced HER2 suppression. Of note, co-incubation with agents that block reactive oxygen species (ROS) production (e.g., N-acetylcisteine) dramatically enhanced the ability of metformin to decrease HER2 expression. From the perspective of chemoprevention, these findings altogether suggest that metformin might exert a protective mostly confined to the HER2-positive breast cancer subtype. From the perspective of intervention, the presence/absence of molecular hallmarks such as HER2 overexpression and/or p70S6K1 hyperactivation might dictate alternative responses in metformin-based treatment of early breast cancer. The importance of mTOR/p70S6K1-sensed ROS status at mediating the anti-oncogenic effects of metformin might represent a previously unrecognized linkage molecularly connecting its anti-aging and anti-cancer actions.
PMID: 19106626

[sarah]

Thanks Lani,
you always come up with interesting breakthroughs.
What does it mean to us HER2ers? at different stages? beginners, intermediate or advanced?
would it be given with Herceptin or do they think it could replace it? is t a pill or intravenous?
thanks
sarah

[MJo]

This has a lot of complex language. My unscientific mind immediately wondered if there is some connection between diabetes or glucose levels and her2 protein.

[RhondaH]

I've thought the SAME thing

[Lani]

from the article it looks as if it might be synergistic with herceptin and perhaps also with mTor inhibitors (several are in clinical trials at the moment)

It is great when an already approved drug with known safety/side effects is found to be helpful as it speeds up the process of combining it with other agents in trials.

Working out how her2, diabetes and aging are all tied in together will keep a lot of researchers busy for quite a while!

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

Oncogene
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.

Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F.


Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

[theresaw]

I am on Metformin thanks to my sugar levels..So does this mean I am not only taking something to help with my diabeties but it is also helping to keep the cancer cells at bay???

[Lani]

they have not yet worked out how much, given how often, with/without herceptin etc to have the effect.

But the good news is...they are working on it!

They would have more funds to work on it if it were not a drug already available and widely used. But, if something is found out, the good news is they don't have to wait years for FDA approval.

Just consider that there is a chance that something you have to take anyway MAY be helping keep your her2 breast cancer at bay.No absolute answers yet

[jml]

I've been taking Metformin for Insulin Resistance for the past 5 years. I'm not diabetic, just insulin resistant-presumably due to chronic exposure to chemotherapies/steroids, etc. I went to see an endocrinologist after my 1st year of treatment, was finally NED & finished w/chemo, but gained 18 lbs in ~4mos. We did a "glucose challenge" & that's how the IR was diagnosed.
Once on the Metformin, I shed the weight (YAY!) & now this news is a TOTAL BONUS!
I've recently explored the option of d/c'ing the Metformin w/my onc, but with this news, I think NOT!

[Alis_hubby]

Unfortunately, metformin is very hard on the liver. I'm not so sure it's an even trade.

Any news about this wonderful drug?

[Cal-Gal]

I read that Metformin was anti-tumor in Life Extension magazine maybe a year ago-this is even better news--

I would love to go on this drug-

[ElaineM]

1. http://search.lef.org/cgi-src-bin/MsmGo.exe?grab_id=0&page_id=598&query=Metformin&hi word=METFORMINS%20Metformin%20
2. http://search.lef.org/cgi-src-bin/MsmGo.exe?grab_id=0&page_id=3015&query=Metformin&h iword=METFORMINS%20Metformin%20
Breast Cancer

Some of metformin’s most compelling effects are in cancers of the reproductive system because it blocks the enzyme called aromatase, which can stimulate estrogen-dependent cancer growth.21 Breast cancer is the most common malignancy diagnosed in women.22 Fortunately, most varieties of breast cancer are proving to be especially susceptible to metformin prevention in the laboratory, and to metformin treatment in human patients, as shown by studies that have emerged over just the past two years.23
Metformin suppresses a specific cancer-inducing protein (human epidermal growth factor receptor 2, or HER2)24 that dramatically increases the risk of breast cancer.25 By suppressing HER2, which can stop cancers from developing in the first place, metformin halts cancer cells’ reproductive cycle, preventing them from growing once they have developed.26
Via a different set of mechanisms, metformin selectively targets cancer stem cells, cells that resist chemotherapy drugs and can regenerate and cause relapse of the disease.27 In live animal studies, metformin suppressed breast cancers, especially in animals on a high-calorie diet.20 In a dramatic 2010 study, metformin extended the life span of mice with HER2-positive breast cancers, delayed the onset of tumor development, and inhibited the growth of implanted tumors.19
The combination of all these effects means that metformin is effective against many different types of breast cancers, including those that are estrogen receptor positive and negative, and those that express both normal and excessive amounts of HER2.28 Indeed, data appeared in 2010 that long-term (greater than 5-year) metformin use by humans is associated with a substantial (56%) reduction in risk for developing breast cancer as compared with no use of metformin.1
Human trials have already demonstrated that diabetic patients with breast cancer who receive metformin plus chemotherapy have a higher rate of complete remission than do those not taking metformin. Complete remission occurred in 24% of diabetic patients taking metformin, 8% of diabetic patients not taking metformin, and 16% of non-diabetic patients not taking metformin.29 And a 2009 study showed that metformin induced unique, multitargeted responses in so-called “triple-negative” breast cancer cells, which represent some of the most difficult-to-treat forms of the malignancy.30
All of these findings speak to metformin’s tremendous potential as a true breast cancer chemopreventive agent—one that can and should be used long before any sign of cancer has appeared. Scientists from around the world believe that the time has come to leverage these effects in breast cancer chemoprevention and treatment.22,23,31,32
What You Need to Know: Metfo

[weety]

Awesome news--keep the info coming!

[pibikay]

Interesting Lani
I am wondering how I missed this wonderfull thred

[Nancy L]

And Metformin is a very inexpensive drug. So if the research shows it would be helpful for all of us, our insurance companies won't say NO to this one.

[weety]

It also has very few major problems associated with its use.

[fullofbeans]

Toxicity profile is very low with 3 out of 100,000 developing lactic acidosis after years o use. Seems to also have gastro implication with 10% stopping because of it.

http://jco.ascopubs.org/content/27/20/3271.full.pdf

A less than $10 month treatment with interesting results.

http://abstract.asco.org/AbstView_102_84233.html
Abstract:
Background: Metformin is associated with a reduced incidence of breast cancer and enhanced response to neoadjuvant chemotherapy in epidemiological studies of diabetic women. Cell line and xenograft studies suggest metformin, widely used in the treatment of diabetes, may be a candidate anti-cancer agent. This randomized phase II neoadjuvant trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer, testing the hypothesis that metformin has anti-cancer effects in women with breast cancer. Methods: Non-diabetic women with operable, primary invasive breast cancer received pre-operative metformin. The trial had two components: a pilot cohort of 8 luminal A patients had core biopsy at three time points: at presentation; a week later without treatment (internal control); then following metformin 500mg o.d. for one week increased to 1g b.d. for a further week up to definitive surgery. A further 47 Luminal A and Luminal B patients had core biopsy measurement at diagnosis, were randomized to metformin or no metformin, and 2 weeks later had core biopsy prior to resection. Ki67 measurements and transcriptome analyses were performed on formalin fixed paraffin embedded tissues. Results: The mean percentage of cells staining for Ki67 fell significantly in both the pilot cohort (p=0.041, paired t-test) and patients randomized to metformin (p=0.027, Wilcoxon rank test) following metformin treatment, but was unchanged in the control arm. By Ingenuity Pathway Analysis, the TNFR1 signaling pathway was most significantly affected by metformin: TGFB, MEKK were commonly up regulated and cdc42 down regulated. The mTOR and AMPK pathways were also significantly affected. By Gene Set Analysis the p53, BRCA1 and cell cycle pathways had reduced expressed following metformin. Conclusions: This window of opportunity trial presents evidence of antiproliferative and anti-cancer effects via specific biomarker pathways for metformin action in primary breast cancer and provides support for further trials testing the use of metformin in the treatment of breast cancer.

[AlaskaAngel]

This is what it takes to find out, in case anyone wants to take part and move the research along.

http://clinicaltrials.gov/ct2/show/N...tformin&rank=1

http://clinicaltrials.gov/ct2/show/N...tformin&rank=2

http://clinicaltrials.gov/ct2/show/N...tformin&rank=3

http://clinicaltrials.gov/ct2/show/N...tformin&rank=4

http://clinicaltrials.gov/ct2/show/N...tformin&rank=5

http://clinicaltrials.gov/ct2/show/N...tformin&rank=6

http://clinicaltrials.gov/ct2/show/N...tformin&rank=7

http://clinicaltrials.gov/ct2/show/N...formin&rank=10

http://clinicaltrials.gov/ct2/show/N...formin&rank=11

-AlaskaAngel