Adipose tissue has long been considered as an « organ » of energy storage. Although many works had previously identified the secretory nature of adipocyte, it was only in 1994, when the leptin gene was cloned, that adipose tissue earned the status of endocrine tissue. It was the first demonstration that an adipose tissue-derived hormone was able to communicate with the central nervous system to control satiety and energy balance. In fact, it is almost at the same time that another major adipokine produced by adipocytes, adiponectin, has been discovered. It took several years to identify the insulin-sensitizing, anti-inflammatory and anti-atherogenic properties of this hormone. More recently, several epidemiological, genetic and experimental findings suggest an anti-carcinogenic role for adiponectin. In this brief review we will present the arguments supporting a protective role of adiponectin in tumor progression, particularly in the context of breast cancer. Adiponectin deficiency commonly observed in obesity may contribute to the natural history of several cancers, as well as the elevation of leptin and other hormonal disturbances associated with excessive adiposity.

It is established that overnutrition is a risk factor for hepatocellular carcinoma. Il has been proposed that hepatic steatosis leads to a subinflammatory response and to the production of mitogenic cytokines. Our team is focused on the role of mammalian Target of Rapamycin (mTOR) in two pathophysiological conditions that modulate liver growth: liver regeneration after partial hepatectomy, and steatosis-associated tumorigenesis. Target kinases of mTOR seem more specifically involved in these processes: while S6K1 contributes to liver regeneration following hepatectomy, Akt2 is implicated in steatosis-associated tumorigenesis. In addition, recent data indicate that the transcription factor PPARγ, through an activation of glycolytic enzymes, could promote liver steatosis, hypertrophy and hyperplasia.

With the better management of cardiovascular risk factors, cancer plays an increasing role in the causes of death among patients with type 2 diabetes. Numerous epidemiological cohort and case-control studies showed that type 2 diabetes is a risk factor for cancer and that metformin therapy is associated with a significant reduction in the incidence of cancer and cancer-related death when compared to other glucose-lowering agents (sulfonylureas, insulin). Such beneficial effect is observed almost whatever the type of cancer, but seems to be more prominent in case of gastrointestinal and breast cancers. Several studies showed a significant relationship between the amplitude of the protection against cancer, on the one hand, and the daily dose of metformin and the duration of exposure, on the other hand. In general, the protective effect was more evident in observational cohort studies (however, more exposed to bias due to confounding factors) than in case-control studies. Several meta-analyses recently confirmed that metformin therapy reduces the incidence of cancers and cancer-related mortality. However, the results of the rather rare controlled clinical trials available are not conclusive, but none of them was performed with the objective to specifically assess cancer risk. Considering all promising clinical information in patients with type 2 diabetes, further clinical trials are currently ongoing with the aim of assessing the role of metformin in oncology, independently of the presence of diabetes.

Recent works suggest that Activin A (ActA) and Myostatin (Mstn), two members of the TGFβ superfamily, could contribute to skeletal muscle atrophy observed in some cancers. It is known that several human tumoral cell lines synthesize and secrete ActA and Mstn. In addition, systemic treatment with ActA and Mstn in mice induce muscle atrophy. Likewise, Inhibin-α knock-out mice, which are characterized by elevated circulating levels of ActA, exhibit muscle atrophy and die of cachexia. Finally, administration of ActA and Mstn antagonists prevents muscular atrophy and mortality induced by some animal tumors. Collectively, these findings suggest that ActA or Mstn production by several cancers could contribute to cachexia and thus to mortality associated with some cancers in human. This hypothesis is very interesting since new molecules that are able to inhibit ActA and Mstn, in particularly the sActRIIB, are under development.

Accumulating recent evidence highlights the tumour-surrounding adipose tissue as a key component of breast cancer progression. We have recently demonstrated that a bidirectional crosstalk is established with breast cancer cells and tumour-surrounding adipocytes. Tumour cell secretions are able to modify tumour-surrounding adipocytes to an activated state that we have named Cancer-Associated Adipocytes (CAAs). The role of CAAs in breast cancer progression, as well as the potential amplification of this negative effect in obesity conditions will be discussed.

Given this widespread role for estrogen in human physiology, it is not surprising that estrogen influence the pathophysiology of numerous diseases, including cancer (of the reproductive tract as breast, endometrial but also colorectal, prostate…), as well as neurodegenerative, inflammatory-immune, cardiovascular and metabolic diseases, and osteoporosis. These actions are mediated by the activation of estrogen receptors (ER) alpha (ERα) and beta (ERβ), which regulate target gene transcription (genomic action) through two independent activation functions (AF)-1 and AF-2, but can also elicit rapid membrane initiated steroid signals (MISS). Targeted ER gene inactivation has shown that although ERβ plays an important role in the central nervous system and in the heart, ERα appears to play a prominent role in most of the other tissues. Pharmacological activation or inhibition of ERα and/or ERβ provides already the basis for many therapeutic interventions, from contraception or hormone replacement at menopause to prevention of the recurrence of breast cancer. However, the use of these estrogens or selective estrogen receptors modulators (SERMs) have also induced undesired effects. Thus, an important challenge consists now to uncouple the beneficial actions from other deleterious ones. We summarize here an in vivo molecular "dissection" that allows to delineate in mouse the role of the main "subfunctions" of the receptor. This could pave the way to an optimization of the ER modulation.

Many epidemiologic studies, with a good methodology, support the evidence of the positive role of regular physical activity on primary and tertiary prevention of breast cancer on the risk of recurrence and mortality. This relation depends on the level of total energy expenditure by week, which helps balance weight on lifetime, an essential part of benefit. The beneficial effects of physical activity are linked to many interrelated additional mechanisms: in a short-term, contraction of skeletal muscles involves aerobic metabolism which utilizes glucose and amino acids like glutamine, improves insulin sensitivity and lowers plasma insulin; in a long-term, physical activity produces favorable changes in body composition, decreasing body fat and increasing lean mass. That is a key point to reduce the intake of energy substrates stimulating carcinogenesis, to improve insulin sensitivity, to change the ratio of leptin and adiponectin, to enhance cellular immunity and to block cellular pathways of cell proliferation and angiogenesis. Maintaining a healthy weight through regular physical activity well balanced with energy intake is it a goal for prevention of breast cancer.

More than one million new cases of breast cancer are diagnosed each year worldwide and more than 400,000 deaths occur due to this pathology. Obesity is a risk factor for postmenopausal breast cancer and the place held by the adipose tissue and secretions (i.e. adipokines) begins to be recognized. Indeed, firstly, plasma adipokine levels, modulated in obesity situation, could have effects "remotely" on mammary carcinogenesis and, secondly, breast cancer cells are surrounded by adipocyte microenvironment, which is probably more important in the case of obesity, and may be locally influenced by it. In this context, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the angiogenesis process and local pro-inflammatory mechanisms, especially in obese patients for whom increased metastatic potential and risk of mortality are described.