Serum Insulin-like Growth Factor-I and Mammary Tumor Development inAd libitum–Fed, Chronic Calorie–Restricted, and Intermittent Calorie–Restricted MMTV-TGF-α Mice

Abstract

The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. Tenweek-old MMTV-TGF-α female mice were assigned to ad libitum-fed (AL; AIN-93M diet), ICR [3-week 50% caloric restriction using AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3 weeks of daily 100% AL consumption of AIN-93M (∼75% of AL for each 6-week cycle)], and CCR (calorie and nutrient intake matched for each 6-week ICR cycle) groups. Half of the mice from each group were sacrificed at 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum was obtained at euthanasia and in cycles 1, 3, 5, 8, and 11. MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICRRestricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. There were no differences in terminal IGFBP-3. Final body, internal, and mammary fat pad weights correlated positively with IGF-I and negatively with IGFBP-3. Few changes were found for protein expression of IGF-IRα and IGFBP-3 in mammary tissue and MTs. During the study, IGF-I levels of ICR-Restricted mice were reduced, whereas refeeding allowed partial recovery. For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR.Worldwide, each year, approximately 1 million women are newly diagnosed with breast cancer (1). This malignancy is second only to lung cancer as a cause of cancer death in women (2). Searching for new ways of prevention and early detection and for physiologic and (or) pathophysiologic markers of breast malignances is a prevalent area of current medical-biological studies.Insulin-like growth factor (IGF)-I is a peptide growth factor with demonstrated roles in mammary gland development (3, 4). Both IGF-I and its primary signaling receptor, IGF-IR, are present in the developing mammary gland (5-8). Additionally, the high-affinity IGF binding protein-3 (IGFBP-3; ref. 9) is also found in this tissue and its expression correlates with specific stages of the progression of mammary epithelial growth and maturation (10). In particular, IGF-I and its signaling pathway (s) have important roles in regulating cellular proliferation, growth, and apoptosis, resulting in interest of this regulatory system to mammary tumorigenesis (11-13).It is interesting to note that laboratory investigation of the relation of IGF-I to mammary/breast cancer was motivated by epidemiologic/clinical research (14). These studies have generally supported an increased risk of breast cancer in association with elevated serum levels of IGF-I in premenopausal women but not in those women who are postmenopausal as summarized in several recent meta-analyse...

Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer

“…The decreased serum leptin levels observed in our study were also observed in the calorie restricted, BK5.COX-2 18 and the MMTV-TGF-a mouse model of breast cancer. 30,31 Taken together, our findings show that both ICR and CCR were effective in delaying the progression of PanIN lesions to PDA and in reducing the incidence of PanIN-2 or greater lesions in LSL-Kras G12D ; Pdx-1/Cre mice. Lanza-Jacoby et al Calorie restriction prevents the development of pancreatic cancer 795 Importantly, ICR had a stronger protective effect on the development of lesions in the LSL-Kras G12D ; Pdx-1/Cre mice than did CCR by completely preventing PanIN-3 lesions.…”

Effects of chronic vs. intermittent calorie restriction on mammary tumor incidence and serum adiponectin and leptin levels in MMTV-TGF-α mice at different ages

“…Interestingly, controlled refeeding had a similar effect to ad libitum refeeding on Mt development, as the Mt incidence of 10% was in the range of 3 and 15% previously reported for Icr mice that were allowed free access to food during refeeding in two earlier longitudinal studies (5,6). Additionally, a recently completed longitudinal study using the controlled refeeding protocol resulted in an Mt incidence rate of 9% for ICR mice compared to 71 and 35% for AL-fed and CCR mice (40). Integration of these findings suggest that the periods of severe restriction associated with the intermittent restriction protocol are important for the protective effect of Icr and that the refeeding aspect of the protocol does not influence the effect to any great degree.…”

Obesity and breast cancer: status of leptin and adiponectin in pathological processes

“…In contrast, diet-induced obese (high calorie diet, fed ad libitum) mice exhibited increased leptin levels [128]. In this connection, our laboratory has been studying the impact No tumor tissue showed overexpression of estrogen receptor β, sex hormone-binding globulin (SHBG), epidermal growth factor receptor (EGFR), and p53 of caloric restriction in mammary tumorigenesis, particularly the protective role of intermittent caloric restriction [129][130][131][132]. In a recently completed study, we found that intermittent caloric-restricted mice had higher serum adiponectin and lower serum leptin levels after 64 weeks of caloric restriction.…”