Breast Cancer Risk and Diabetes Mellitus Type 2

Upper body obesity and the related metabolic disorder type 2 diabetes have been
identified as risk factors for breast cancer, and associated with late-stage disease and poor prognosis. Components of the MeS, including visceral adiposity, insulin resistance,hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus type 2, low serum HDL cholesterol and hypertension have all been
related to an increased risk of breast cancer [10]. One of the hallmarks of aggressive cancer cells is a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA. The breast cancer gene 1 (BRCA-1) stabilizes the inactive (phosphorylated) form of the acetyl coenzyme A carboxylase , the rate-limiting enzyme catalyzing de novo fatty acid biogenesis. Therefore, one mode of action of BRCA-1 is a tumor suppressor activity which depends on its ability to mimicry a cellular low-energy status, which is also known to block tumor cell anabolism and suppress the malignant phenotype. It is interesting to see that physical activity and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA-1 gene mutations [11].
The adipocytes, forming the belly fat, are now in the focus of metabolic research in
oncology. Adipocytes produce adipocytokines, which are biologically active polypeptides and act by endocrine, paracrine, and autocrine mechanisms; most have been associated with MeS. Six adipocytokines – vascular endothelial growth factor, hepatocyte growth factor, leptin, tumor necrosis factor-, heparin-binding epidermal
growth factor-like growth factor, and interleukin-6 – promote angiogenesis. Obesity
and insulin resistance, again, have been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis [12]. However, the picture is not as clear as to be expected because a case-control study in Chile did not show any association between obesity and breast cancer at any age, although the same study revealed that insulin resistance was independently associated with breast cancer in postmenopausal women, but not in premenopausal women [13].
Insulin growth factors (IGFs) are important mediators of growth, development,
differentiation and survival of normal and transformed cells. Recent studies confirmed the association between serum levels of IGF-1 and diverse malignant diseases, while some relationships with other pathologies since diabetes mellitus type 2 have been described. Currently, IGFs are considered important targets for the study of new therapeutic drugs and strategies for cancer treatment [14].
A meta-analysis of case-control (n
5) and cohort studies (n
15) to assess the
evidence regarding the association between diabetes and risk of breast cancer yielded
a summary RR of 1.24 for women with (versus without) diabetes. Findings from this
The Epidemiologic Relationship between Diabetes and Cancer 87
meta-analysis indicate that diabetes is associated with an increased risk of breast cancer
[15]. However, it is important to know for diagnostic purposes that, although the
breast cancer risk is increased among women with type 2 diabetes, type 2 diabetes
does not significantly influence mammographic breast density [16].
The role of diabetes in the etiology of breast cancer in Asian-Americans is of special
interest because of their consumption of soy. A population-based case-control
study in Los Angeles County that included 1,248 Asian-American women with incident,
histologically confirmed breast cancer and 1,148 control women, who were frequency
matched to cases on age, Asian ethnicity and neighborhood of residence,
showed that the diabetes-breast cancer association was observed only in low/intermediate
soy consumers but not among high soy consumers [17].
Another question is becoming increasingly common: How does gestational diabetes
relate to future risk of disease? The Jerusalem Perinatal Study, including 37,926 women,
suggests that gestational diabetes may be an important early marker of breast cancer risk
among postmenopausal women; however, the authors clearly state that these results
need to be confirmed in future studies [18]. Another study in Israel revealed after adjustment
for body mass index that breast cancer among diabetic patients was more often
hormone receptor negative [19]. Population-based health databases from Ontario,
Canada, used for retrospective cohort studies showed that diabetes was associated with
a close to 40% increase in mortality within the first 5 years following breast cancer,
which means that early survival following breast cancer is reduced in women with diabetes
[20]. Results from the same databases indicate that women with diabetes were less
likely to have a mammogram during a 2-year period than were women without diabetes,
despite more healthcare visits. These findings highlight the need for better organization
of primary care for patients with chronic diseases, like diabetes and/or cancer [21].
It has been recently shown that activation of the AMP kinase pathway is necessary
for metformin to inhibit gluconeogenesis in hepatocytes. This pathway is also
involved in metformin-induced growth inhibition of epithelial cells. Breast cancer
cells escape metformin-induced growth inhibition by small interfering RNA against
AMP kinase. These results provide evidence for a mechanism that may contribute to
the antineoplastic effects of metformin suggested by some population studies and
stress the potential role for activators of AMP kinases in (breast) cancer prevention
and treatment [22, 23].