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 DMBAinduced mammary tumors, suggesting that adipose tissuederived 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 is associated with increased risk for postmenopausal breast cancer. Clinical data suggest that women with Estrogen Receptor negative (ER−) breast cancer have poorer outcome than those with ER+ tumors. The main objective of this study was to investigate whether obesity can be associated with the expression of ER in mammary tumors in the presence or absence of ovarian estrogen. Lean and obese Zucker rats were sham operated or ovariectomized at age 40 days and were gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly for detection of mammary tumors and killed 135 days post‐DMBA treatment. ER immunohistochemistry was performed on paraffin‐embedded tumors. The incidence of mammary tumors was 59% in the obese, sham‐operated (O/S) rats compared to 30% in the lean sham‐operated (L/S) group (P<0.05) and 36% for the obese ovariectomized (O/O) rats while no lean ovariectomized (L/O) rats developed tumors (P<0.001). ER expression was evaluated for all the ductal carcinoma in situ (DCIS) or invasive ductal and lobular carcinoma (IDC) tumors and the results are as follows; L/S group (17% ER – and 83% ER+), O/S group (45% ER− and 55% ER+) and O/O groups had 50% ER− and 50% ER +. These preliminary results suggest that obesity may increase the incidence of ER negative tumors in the obese Zucker rat DMBA mammary tumor model (Supported by Susan G. Komen Breast cancer foundation and ABI to RH)
Obesity is associated with increased risk for post‐menopausal women. Several studies have suggested that IGF‐1 plays an important role in promotion and progression of breast cancer. The main objective of this study was to use DMBA‐induced ovariectomized obese zucker rat model to investigate the effects of obesity on serum IGF‐1 levels. Lean and obese rats were sham operated or ovariectomized at age 40 days and were gavaged at age 50 days with 65 mg/kg DMBA. Rats were killed 135 days post‐DMBA treatment. Serum IGF1 was measured by ELISA. Thirty‐six (36%) of the obese ovariectomized rats (O/O) developed mammary tumors while lean ovariectomized (L/O) rats developed no mammary tumors (P<0.001). The obese sham (O/S) rats developed mammary tumors (59%) compared to 30% of the lean sham (L/S) rats (P<0.05). Ovariectomy caused a significant (P<0.001) increase in serum IGF‐1 for ovariectomized lean group but not in obese group. Also, obesity significantly increased (P<0.001) serum IGF‐1 in both sham and ovariectomized rats compared to lean rats. Our results suggest that obesity is a major risk for DMBA‐induced mammary tumor development and elevated IGF‐1 levels may be associated with the increased susceptibility to DMBA‐induced mammary tumors. Other mechanisms responsible for increased mammary tumor susceptibility in obese rats are under investigation. (Supported by Susan G. Komen Foundation and ABI to RH).
Human and animal studies have suggested that obesity can play important role in promotion of fatty liver. Recently, we have reported that short‐term soy protein diet can reduce fatty liver. The main objective of this experiment was to investigate the long‐term effects of obesity and soy diet on liver steatosis using 7,12‐dimethylbenz(a)anthracene (DMBA)‐Induced mammary tumors in an ovariectomized obese zucker rat model. treatment. Ovariectomized lean (n=56) and Obese (n=60) Zucker rats were maintained on either casein or soy protein diet from one week before and until 155 days after DMBA treatment. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Our results demonstrated obesity caused a significant increased on liver weight (P<0.05) and soy diet reduce liver weight in lean and obese group (P<0.05). Obesity caused a significant increase in fatty liver steatosis with rats fed casein diet had marked steatosis with small foci of mononuclear infiltration (P<0.05) but soy‐fed lean (1.00±0.0) and obese (3.20±0.26) rats significantly had lower steatosis than casein‐fed lean (1.96±.16) and obese (4.42±.10) rats. Our results suggest that long‐term dietary soy treatment can protects against liver steatosis in lean and obese ovariectomized animals. The mechanisms responsible for increasing fatty liver steatosis in obese rats are under investigation.
We reported that intact obese Zucker female rats fed semi‐purified diets were protected against DMBA‐induced mammary tumor on the casein but not soy diet. We investigate the effects of long‐term soy vs casein protein intake and obesity on plasma isoflavones levels. Five‐week‐old female Zucker rats were used. After one week of acclimation (age 42 days), rats were randomly assigned to; 1) Lean, casein; 2) Obese, casein; 3) Lean, soy and 4) Obese, soy. Rats had ad lib access to water and diet with either casein or soy protein isolate. Rats were orally gavaged at age 50 days with 65 mg/kg DMBA and sacrificed 155 days later. Plasma were collected to measure genistein, daidzein, glycitein, equol and O‐Desmethylangolensin (O‐MDA) (n=5/group). At end of the experiment, 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176). In the obese group, 76% of the soy‐fed rats developed mammary tumors compared to 15% (P<0.001) of obese casein‐ fed rats. Plasma daidzein and genistein concentration were not significantly different in lean vs obese soy‐fed rats. However, O‐MDA and equol concentration were significantly lower in obese soy‐fed rats compared to lean soy rats. These data suggests that obese and lean Zucker rats have different intestinal flora which may impact DMBA‐induced mammary tumor development. (Supported by USDA and ABI to RH)
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