(1)H nuclear magnetic resonance metabolomic analysis of mammary tumors from lean and obese Zucker rats exposed to 7,12-dimethylbenz[a]anthracene.

Obesity increases mammary tumor development in Zucker rats following a single administration of the procarcinogen 7,12-dimenthylbenz(a)anthracene (DMBA). Fifty-day-old obese and lean female Zucker rats were orally gavaged with 65 mg/kg DMBA and sacrificed 139 days post DMBA treatment. At the end of the experiment, mammary tumors were detected in 68% of the obese rats compared to 32% of the lean group (P<0.001). 1H nuclear magnetic resonance (1H-NMR) spectra obtained for hydrophilic and lipophilic extracts from excised tumors illustrated fundamental differences in metabolic profiles between the two groups. Differences were observed for key choline compounds, namely phosphocholine and glycerophosphocholine, both markers of malignancy and apoptosis. In addition, levels of lactate, creatine, myo-inositol, alpha-glucose, alanine, leucine, glutamate, glutamine, tyrosine, phenylalanine, and NADH varied between the lean and obese groups. Principal component analysis indicated class separation between tumors from lean and obese rats based on their metabolic profiles, illustrating the potential for using 1H-NMR metabolomic methods for identifying altered metabolic pathways. Our results suggest that obesity enhances the risk for DMBA-induced mammary tumor development in rats. However, the mechanism for this increase in risk is currently unknown and will require further studies for elucidation.

Obesity increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in an ovariectomized Zucker rat model.

Obesity is associated with increased risk for postmenopausal, but not premenopausal breast cancer. Recently, we reported that intact obese Zucker rats had increased susceptibility to DMBA-induced mammary tumors compared to lean Zucker rats. In the present study, we investigated whether excessive adipose tissue would promote mammary tumor induction in the absence of ovarian estrogen. Lean and obese rats were sham-operated or ovariectomized at 40 days old and were gavaged at 50 days old with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors and sacrificed 135 days post-DMBA treatment. Obese sham-operated (O/S) rats had a shorter latency period (102 days) compared to lean sham-operated (L/S) (134 days) and obese ovariectomized (O/O) rats (123 days). At the end of the experiment, 36% of the O/O rats developed mammary tumors while lean ovariectomized (L/O) rats developed no mammary tumors (P<0.001), and 59% of the O/S rats developed mammary tumors compared to 30% of the L/S rats (P<0.05). In summary, obesity increases the susceptibility of ovariectomized Zucker rats to DMBA-induced mammary tumors, suggesting that adipose tissue-derived estrogen in obese animals may be sufficient to promote DMBA-induced tumors in this model. These results suggest that obesity in postmenopausal women may increase breast cancer risk due to increased breast tissue exposure to adipose tissue-derived estrogen. In conclusion, we have developed an animal model to further investigate the role of obesity in breast cancer development in postmenopausal women.

Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats.

INTRODUCTION: High body mass index has been associated with increased risk for various cancers, including breast cancer. Here we describe studies using 7,12-dimethylbenz(a)anthracene (DMBA) to investigate the role of obesity in DMBA-induced mammary tumor susceptibility in the female Zucker rat (fa/fa), which is the most widely used rat model of genetic obesity. METHOD: Fifty-day-old female obese (n = 25) and lean (n = 28) Zucker rats were orally gavaged with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors. Rats were killed 139 days after DMBA treatment. RESULTS: The first mammary tumor was detected in the obese group at 49 days after DMBA treatment, as compared with 86 days in the lean group (P < 0.001). The median tumor-free time was significantly lower in the obese group (P < 0.001). Using the days after DMBA treatment at which 25% of the rats had developed mammary tumors as the marker of tumor latency, the obese group had a significantly shorter latency period (66 days) than did the lean group (118 days). At the end of the study, obese rats had developed a significantly (P < 0.001) greater mammary tumor incidence (68% versus 32%) compared with the lean group. The tumor histology of the mammary tumors revealed that obesity was associated with a significant (P < 0.05) increase in the number of rats with at least one invasive ductal and lobular carcinoma compared with lean rats. CONCLUSION: Our results indicate that obesity increases the susceptibility of female Zucker rats to DMBA-induced mammary tumors, further supporting the hypothesis that obesity and some of its mediators play a significant role in carcinogenesis.