Exp Clin Endocrinol Diabetes. 2010 Nov;118(10):673-7. Epub 2010 Jun 8.
University Hospital Heidelberg, Department of Gynecology and Obstetrics within the National Center for Tumor Diseases, Heidelberg.
Breast cancer is the leading neoplastic malignancy among females worldwide. Another major health problem in industrial countries is diabetes mellitus type 2, both with a raising tendency. Up to 16% of the elderly breast cancer patients additionally suffer from diabetes. Epidemiologic studies suggest that type 2 diabetes increases breast cancer risk and goes along with an increased mortality however, there has been limited experimental evidence supporting this association. In the present review we summarized epidemiological data on a correlation between diabetes and breast cancer. Further, the diverse hypothesized molecular investigations and purposed mechanisms are recapitulated. The latest discussions on insulin and its enhancement of cancer rates among patients with diabetes have also toughed the breast cancer sector. In contrary, recent data indicate a benefit of breast cancer treatment due to metformin therapy. A large amount of literature is available and provides concepts for future research that is needed to rule out possible overlapping pathomechanism, prognostic factors, therapy interactions as well as possible synergistic or additive or even controversial interaction of chemotherapy and diabetes medication.
AND TAKE YOUR METFORMIN!
Med Oncol. 2010 May 20. [Epub ahead of print]
More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin.
N. N. Petrov Research Institute of Oncology, Pesochny-2, 197758, St. Petersburg, Russia, firstname.lastname@example.org.
The coexistence of type 2 diabetes with breast cancer may result in poorer cancer-related survival due to a number of mediating factors including an alteration of tumor tissue hormonal sensitivity. Previous studies have shown that receptor status of breast tumors in diabetics may be changed; however, the mode of therapy for diabetes was usually ignored. This work presents the results of an analysis of the receptor status of breast carcinomas in 90 postmenopausal women suffering with diabetes mellitus type 2 who had been cured, for not less that 1 year prior to surgery, with different modes of antidiabetic therapy, including a dietary treatment only, sulfonylurea preparations, insulin therapy, and metformin as a monotherapy or in combination with sulfonylurea derivatives. No differences in estrogen receptors occurrence in tumor tissue were found in different treatment groups. The frequency of progesterone receptor-positive mammary carcinomas in women who were treated with metformin, irrespective of whether it was combined with sulfonylurea preparations, was significantly higher than in the sulfonylurea only group (P = 0.043) and in the combined group of patients treated with either sulfonylurea or insulin (P = 0.041). The exclusion of the patients who received neoadjuvant chemotherapy (24 persons) did not significantly affect the above results. The data may be used as an explanation of the distinctions in cancer characteristics and course between diabetic patients treated with either metformin or sulfonylurea derivatives and insulin.
AND HERE IS A BIT OF HISTORY
Cell Cycle. 2010 Mar 21;9(6). [Epub ahead of print]
Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute (IdIBGi), Girona, Catalonia, Spain.
In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs (“metabolic rehabilitation”). In the early 2000s, Anisimov’s experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients’ survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel “hybrid anti-cancer pill” physically combining both the long-lasting effects of antibodies-by persistently lowering levels of blood insulin and glucose-and the immediate potency of a cancer cell-targeting molecular agent-by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin’s mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin’s ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin’s ability to kill the “dandelion root” beneath the “cancer soil” likely exceeds metformin-related dangers of hormesis.
Med Hypotheses. 2009 Oct;73(4):606-7. Epub 2009 Jun 27.
Is it the time for metformin to take place in adjuvant treatment of Her-2 positive breast cancer? Teaching new tricks to old dogs.
Division of Endocrinology and Metabolism, Ege University School of Medicine, 35100 Izmir, Turkey. email@example.com
Breast cancer is the most common malignancy diagnosed among women. According to the new molecular subclassification, basal like and Her-2 positive breast cancers have the worst outcome and these are the ones in which chemotherapy is a must as a part of adjuvant treatment. New treatment options that could be used as an adjuvant maintenance treatment are still being investigated. Insulin hormone is one of the reasons of breast cancer recurrence and death in breast cancer survivors. Targeting insulin as a therapeutic modality in breast cancer could be an option in the adjuvant treatment of breast cancer. It seems that insulin may signal to activate a cascade of proliferative and anti-apoptotic events in the cancer cell. Metformin, an oral anti-diabetic known for 50 years, may also have direct effects on cancer cells. Metformin causes Her-2 suppression via the inhibition of mTOR in breast cancer cells. Thus, we believe that the time has arrived both to target insulin reduction and to alter Her-2 oncogene based molecular pathogenetic steps in breast cancer by using metformin as an adjuvant therapy in breast cancer patients.