PPAR ligands as potential modificators of breast carcinoma outcomes

Mohammed Jarrar, Ancha Baranova

Our thoughts related to the topic were published in:

J Cell Mol Med. 2007 Jan-Feb;11(1):71-87.

and

PPAR Res. 2008; 2008: 230893

Chemically synthesized ligands for nuclear receptors of the PPAR family modulate a number of physiological functions, particularly insulin resistance in the context of energy homeostasis and the metabolic syndrome. Additionally, these compounds may treat or prevent the development of many secondary consequences of the metabolic syndrome. Many PPAR agonists are also known to influence the proliferation and apoptosis of breast carcinoma cells. It is likely that the breast epithelium of diabetics exposed to PPAR agonists will experience perturbation of the corresponding signaling pathway. Consequently, these patients’ lifetime breast carcinoma risks could be modified, as their breast lesion incidence or the rates of the malignization of these lesions might vary upward or downward. PPAR activating treatment may also influence the progression of existing, undiagnosed invasive lesions.

Recently, the universe of chemical compounds commonly encountered by current and future breast carcinoma patients has been enriched by a number of pharmacotherapeutic agents being prescribed as a lifelong support for common chronic diseases. Depending on the particular molecular pathways which these agents modulate, they may initiate malignization of breast epithelia, stimulate proliferation and invasion of existing tumor cells, or, on the contrary, prevent the tumor’s development. For example, type II diabetes patients are routinely treated with chemically synthesized ligands for PPARγ, thiazolidinedione (TZDs), namely pioglitazone (Actos, Takeda/Lilly), and rosiglitazone (Avandia, GlaxoSmithKline). The glucose-lowering effects of these compounds are mediated primarily by decreasing insulin resistance and increasing glucose uptake by the skeletal muscles. In addition, TZDs suppress glucose production in the liver. These and other beneficial effects rapidly made TZDs a mainstream diabetes therapy.
TZDs are also known to suppress the proliferation and induce apoptosis of breast carcinoma cells in vitro. It is likely that the breast epitheliums of diabetics exposed to TZDs will experience perturbation of the PPAR signaling pathway. Consequently, current or past TZD users’ lifetime breast carcinoma risks may be modified, as their breast lesion incidence or rates of the malignization of lesions might change upward or downward. TZD treatment may also influence the progression of existing undiagnosed invasive lesions.
Ligands to other PPARs, particularly PPARα and PPARδ,, are currently being explored as potential cardiovascular therapeutics and metabolic syndrome alleviation agents. It is very possible that in the next two or three decades the number of women exposed to PPAR ligands may reach 10-15 million in the USA alone. If PPAR ligands indeed modify breast carcinoma incidence and outcomes, the effects of chronic exposure to these compounds will translate into statistically significant changes visible in epidemiological survey data, similar to those seen in cohorts taking hormone replacement therapy..

Figure 1. A summary of influence of PPAR ligands on the process of breast carcinogenesis.