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

Olga P. Rogozina; Melissa J.L. Bonorden; Joseph P. Grande; Margot P. Cleary

doi:10.1158/1940-6207.CAPR-09-0028

DOI: 10.1158/1940-6207.CAPR-09-0028 Published August 2009

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Fig. 1.
Body weight curves of TGF-α female mice over the course of the experiment. ▪, AL (n = 25-73 depending on age); ▴, ICR (n = 29-73 depending on age); ▾, CCR (n = 31-74 depending on age). P < 0.0001, ANOVA; AL group was significantly different (P < 0.001) from ICR and CCR groups, whereas there was no difference between the ICR and CCR groups.
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Fig. 2.
Terminal IGF-I and IGFBP-3 serum level and ratio of IGF-I:IGFBP-3 of TGF-α female mice. A, terminal IGF-I serum levels. P = 0.0001, ANOVA. AL (n = 38), CCR (n = 37), ICR-Refed (n = 19), and ICR-Restricted (n = 30) mice. B, terminal IGFBP-3 serum levels. P = 0.0001, ANOVA. AL (n = 25), CCR (n = 26), ICR-Refed (n = 12), and ICR-Restricted (n = 13) mice. C, ratio of IGF-I to IGFBP-3 levels. P = 0.01, ANOVA. AL (n = 18), CCR (n = 26), ICR-Refed (n = 12), and ICR-Restricted (n = 12) mice. In A to C, ICR-Refed mice were euthanized during a refeeding period and ICR-Restricted mice were euthanized during a restriction period. Columns with different superscripts are significantly different from each other.
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Fig. 3.
Serum IGF-I levels for AL, CCR, and ICR TGF-α mice with and without MTs over the course of the study. A, serum IGF-I serum levels for AL mice during cycles 1, 3, 5, 8, and 11 for mice that never developed MTs (white columns) compared with those that did (black columns). Columns, mean of IGF-I concentrations. P < 0.05, ANOVA. AL without MTs (n = 24) and AL with MTs (n = 24). B, serum IGF-I serum levels for CCR mice during cycles 1, 3, 5, 8, and 11 for mice that never developed MTs (white columns) compared with those that did (black columns). P < 0.01, ANOVA. CCR without MTs (n = 24) and AL with MTs (n = 42). *, significant difference by χ² analysis between IGF-I serum levels for mice with versus without MTs in A and B. C, serum IGF-I serum levels for ICR-Restricted (gray columns) versus ICR-Refed (hatched columns). P < 0.01, ANOVA. Columns, mean of IGF-I concentrations for ICR mice without MTs. ICR after restriction (n = 20) and ICR after refeeding (n = 20). Numbers above the columns, means of IGF-I for ICR mice with MTs (n = 4). Lines, IGF-I serum levels for AL and CCR mice without MTs. *, significant difference by χ² analysis between IGF-I serum levels for ICR mice in Restriction versus Refeeding.
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Fig. 4.
Protein expression of IGFBP-3 and IGF-IRα in MT and mammary tissue. A, IGFBP-3 and IGF-IRα protein expression levels were detected by Western blot analysis. β-Actin protein was probed as a loading control. B, expression of IGFBP-3 in MTs of TGF-α mice. C, expression of IGFBP-3 in mammary tissue of TGF-α mice. ICR-Refed mice were euthanized during a refeeding period, and ICR-Restricted mice were euthanized during a restriction period. *, values within a column with different superscript symbol are significantly different by χ² analysis. D, expression of IGF-IRα in MTs of TGF-α mice. E, expression of IGF-IRα in mammary tissues of TGF-α mice. ICR-Refed mice were euthanized during a refeeding period, and ICR-Restricted mice were euthanized during a restriction period.

Table 1.

Final body, fat pad weights, and MT characteristic for AL, CCR, and ICR TGF-α female mice

	AL (n = 69)	CCR (n = 65)	ICR (n = 59)
	AL (n = 69)	CCR (n = 65)	ICR-Refed (n = 29)	ICR-Restricted (n = 30)
Final body weight (g)	33.79 ± 0.71^*	27.19 ± 0.36	27.38 ± 0.50	24.27 ± 0.50
Mammary fad pad weight, g (combined right and left mammary fat pads)	1.77 ± 0.11^*	0.87 ± 0.04	0.86 ± 0.07	0.35 ± 0.06
Internal fat pad weight, g (combined parametrial and retroperitoneal fat pads)	2.27 ± 1.37^*	0.93 ± 0.47^*	1.01 ± 0.0.08	0.48 ± 0.03

	AL (n = 69)	CCR (n = 65)	ICR (n = 66)
Age of MT detection (wk)	61.0 ± 1.1^*	69.0 ± 1.6	67.0 ± 4.2^*
% of mice in group with MT (number with MT/total mice)	71.0% (69/49)^*	35.4% (65/23)	9.1% (66/6)
MT weight (g)	0.93 ± 0.11	0.43 ± 0.04	0.66 ± 0.38
No. MTs/mouse (average in tumor-bearing mice)	1.82 ± 0.17^*	1.39 ± 0.18	1.00
Total (no. MTs)	89	32	6
Low grade and a carcinoma in situ (number/%)	5/5.6%	2/6.3%	1/16.7%
Grade 2 (number/%)	76/84.3%	27/84.3%	4/66.6%
Grade 3 (number/%)	9/10.1%	3/9.4%	1/16.7%