Obesogenic and leptogenic nutrient sensing pathways of p27Kip1: implication in breast cancer.

Abstract #5035 Background: The U.S. National Cancer Institute currently lists obesity as one of the leading factors that increase the risk of developing breast cancer. Also it has been known since 1909 that, in rodents, caloric/dietary restriction is a potent and highly reproducible way to prevent various types of cancer, including mammary adenocarcinoma. However, the molecular mechanisms of how obesity or caloric/dietary restriction modulates the risk of developing breast cancer are not known. Objective : Objective of this study is to identify such molecular mechanisms. In our previous study, several nutrient sensing pathways that are highly likely to modulate the risk of developing breast cancer were identified using human breast cancer cell lines that were transfected with luciferase reporter construct of 59-untranslated region of p27Kip1 gene. In the present study, we investigated the activity of these nutrient sensing pathways in the rodent models of obesity and hormonal dwarfism, a genetic model of caloric/dietary restriction. Methods: Three rodent models of obesity were used, namely (a) leptin receptor-deficient female obese Zucker rats, (b) leptin-deficient female ob/ob mice and (c) 60% fat diet-induced female obese mice. It was previously reported that the incidence of carcinogen-induced mammary adenocarcinoma is significantly higher in obese Zucker rats compared to the wild-type lean Zucker rats. For rodent model of hormonal dwarfism, we used long-lived female Ames dwarf mice. These mice are very similar to the mice subjected to caloric/dietary restriction; they are resistant to various type of cancer and live significantly longer than normal controls. The nutrient sensing pathways of p27Kip1 were investigated using three different methods, namely (a) blood metabolite analysis, (b) western immunoblot analysis, and (c) proteomic analysis. The livers were used for the latter two analyses because we were interested in investigating the nutrient sensing pathways upstream of p27Kip1. Results and Discussion: Obesogenic Nutrient Sensing Pathways of p27Kip1 – The obesogenic nutrient sensing pathways of p27Kip1 were detected in two rodent models of obesity, namely (a) leptin receptor-deficient obese Zucker rats and (b) leptin-deficient ob/ob mice. These pathways were not detected in the 60% fat diet-induced obese mice. One of the pathways consisted of (a) glucose → (b) AMP/ATP ratio → (c) 59AMP-dependent kinase (AMPK) → (d) tuberous sclerosis complex (TSC) protein → (e) mammalian target of rapamycin (mTOR) → (f) translation initiation repressor protein 4E-BP1 → (g) p27Kip1→ (h) inceased risk of breast cancer. Another pathway consisted of (a) growth factors (including insulin) → (b) receptor tyrosine kinases (RTKs) → (c) phosphoinositide-3-kinase (PI3K) → (d) Akt/PKB → (e) TSC → (f) mTOR → (g) 4E-BP1 → (h) p27Kip1 → (i) increased risk of breast cancer. Leptogenic Nutrient Sensing Pathways of p27Kip1 – The leptogenic nutrient sensing pathways of p27Kip1 were detected in the long-lived Ames dwarf mice. These pathways were the same as those of obesogenic nutrient sensing pathways except that the amount, ratio or phosphorylation of the intermediates was reversed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5035.