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Department of Animal and Range Sciences, North Dakota State University, Fargo, ND 58105
4To whom correspondence should be addressed. E-mail: c.park{at}ndsu.nodak.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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46% (P < 0.05) and 27% (P = 0.07) higher in the CNR group than in the control during late gestation and early lactation of the first lactation cycle, respectively. Caspase-3 enzyme activity was decreased 15% (P < 0.05) and 22% (P = 0.11) in mammary tissues from the CNR group compared with that from the controls during the first and second lactation cycles, respectively. These results indicate that compensatory growth induced only once during late gestation increases mammary cell proliferation and differentiation and decreases regression of mammary cells throughout consecutive lactation cycles.
KEY WORDS: • compensatory growth • mammary cell proliferation • apoptosis • lactation • rats
Mammary growth is a major determinant of milk yield capacity and longevity of lactation (1,2). In growing animals, abnormal feeding intensity (i.e., overfeeding or excessive restriction) imposed during hormone-dependent developmental stages (i.e., puberty through gestation) is likely to affect mammary development and the succeeding lactation (1). Our laboratory developed a stair-step compensatory growth regimen, which is a nutrition program with a unique combination of alternating dietary energy restriction and realimentation phases designed to induce compensatory mammary growth during distinct developmental periods. This nutrition model was tested using a number of animal species including female rats (3–6), gilts (7), and heifers (8–10); most of these works were reviewed (11). Our studies (11) as well as those of others (12–14) showed consistently that multistep nutrition regimens implemented during peripuberty through gestation enhance mammary growth and lactation performance. However, these multistep models are rather complex and labor intensive. Therefore, we proposed simplified one-step models. Although the one-step regimen examined during the pubertal period is effective (4), the present study focused on gestation. The gestational period may be the most critical stage of mammary development and the most sensitive to energy modulation. Depending on the species, between 48 and 94% of total mammary growth occurs during gestation (15). In rats, 65% of the total mammary parenchymal growth takes place during pregnancy (16). The primary concern of this research was to study the efficacy of compensatory mammary growth induced only once during gestation upon mammogenesis and the succeeding lactation performance of female rats.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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25°C and 50% relative humidity with a 12-h light:dark cycle and free access to water. All experimental methods and procedures were approved by the University Animal Care and Use Committee. Rats had free access to the control diet (AIN-93G) (17) during a 3-wk acclimation period. During wk 3 of the acclimation period, rats (4 females/male) were caged for 3 nights with proven breeders. The presence of sperm in a vaginal smear was considered d 1 of gestation. Rats failing to conceive during the 7-d mating period were deleted from the experiment. After mating, rats were grouped by gestational length and then randomly assigned within the gestational age group to either the control or the compensatory nutrition regimen (CNR)5 group.
Control rats were offered free access to the control diet throughout the trial period. CNR rats were subjected to dietary energy restriction during the first 10 d of gestation followed by dietary energy realimentation (free access to control diet) for the remainder of gestation. The energy-restricted diet was formulated to provide an intake of protein, vitamins, and minerals similar to that of the control group; only the energy content was lower (Table 1). CNR rats were fed the energy-restricted diet at 60% of the mean intake consumed ad libitum by the control group, i.e., if the control group consumed 10 g/d, the amount of feed offered to the restricted group was 6 g/d. Feed intake was recorded every other day during the 10-d energy restriction period to adjust the intake of the treatment group. Rats were weighed at the onset of the trial and every 2 d during gestation.
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14 wk of age), all rats were offered free access to the control diet until fulfillment of the first lactation cycle. The day on which a litter was found was designated as d 1 of lactation. Litter size in both groups was adjusted to 8 pups/dam on d 3 of lactation. Dams and litters were weighed on d 3, 10, and 18 of lactation. Milk yield on d 18 of lactation was determined by a stepwise forward multiple regression equation as described previously (18). Two weeks after weaning, dams were mated again and offered free access to the control diet throughout the entire second lactation cycle. Rats were killed by CO2 overdose for mammary tissue collection at different physiologic stages, i.e., 2 rats per treatment group were killed during realimentation (d 18 of gestation), and 4 rats per treatment group were killed during early (EL; d 3) and late (LL; d 18) stages of both lactation cycles. Subsamples of mammary tissues were homogenized in denaturing solution for RNA extraction and Northern analyses. Remaining tissues were frozen and stored at -70°C for caspase-3 enzyme assay.
Cell proliferation by immunohistochemistry. Rats from each treatment were randomly selected and injected i.p. with bromodeoxyuridine (BrdU, a thymidine analog; 5 mg/kg body weight; Aldrich) during late gestation (d 18) and EL (d 3). Two hours after BrdU injection, rats were killed by CO2 overdose; a small portion of mammary tissue from the fifth left mammary gland was collected, fixed in Carnoy’s fixative for 4 h, transferred to 70% ethanol, embedded in paraffin, sectioned at 5 µm, and mounted onto glass slides. Mammary cell proliferation was determined immunohistochemically by using a specific monoclonal antibody and indirect immunoperoxidase detection via the avidin:biotinylated peroxidase complex (ABC) method (Vector Laboratories) as described previously (4). Modifications to the previous method include increasing the incubation time with mouse anti-BrdU monoclonal antibody (Boehringer Mannheim; 2 mg/L in blocking buffer) to 90 min and increasing the incubation time with biotinylated mouse IgG serum and ABC complex to 45 min each. Peroxidase substrate SG (Vector Laboratories) was used in the color development. Sections were counterstained with Nuclear Fast Red to visualize labeled nuclei.
BrdU staining was observed by light microscopy. A photomicrograph (200X) was taken of each of 4 randomly chosen fields (1000–1500 nuclei/field) per slide per rat. Labeled and unlabeled nuclei on the total area of each photomicrograph were counted. The labeling index was calculated as the percentage of BrdU-labeled nuclei relative to the total number of nuclei.
Caspase-3 enzyme activity. The CaspACE Assay System (Promega) was used to measure the caspase-3 activity in tissue. Whole frozen mammary tissues collected during LL (d 18) of both lactation cycles were ground in liquid nitrogen. Ground tissue (1 g) was homogenized in 5 volumes of PBS and centrifuged at 15,800 x g for 10 min at 4°C. The supernatant was diluted 20 times with PBS.
A calibration curve was prepared by serially diluting the 100 mmol/L stock solution of p-nitroaniline (pNA). Assay buffer and 200 µmol/L Asp-Glu-Val-Asp-pNA substrate were added to 10 µL of tissue homogenate in a 96-well microplate. The plate was sealed with parafilm and incubated at 37°C for 4 h. The absorbance was measured at 405 nm on a plate reader. Caspase-3 activity of tissue homogenates was obtained by regression equation constructed from the standard calibration curve. The bicinchoninic acid protein assay reagent kit (Pierce) was used to detect total soluble protein in the tissue homogenates. Caspase-3 specific activity was calculated as pmol/µg protein.
Northern and dot blot analysis. Total RNA was extracted from fresh mammary tissues using Tri Reagent (Sigma) according to manufacturer’s instructions. For dot blotting, total RNA from individual mammary tissues was dotted directly onto nylon membranes as previously described (3). For Northern blotting, pooled total RNA was fractionated by electrophoresis (10 µg/lane) on agarose gels containing 2.2 mmol/L formaldehyde and then transferred to nylon membranes.
The membranes were baked for 1 h in a vacuum oven at 80°C and then hybridized with cDNA probes: rat ß-casein [donated by Dr. J. Rosen, Baylor College of Medicine, Houston, TX] and rat ornithine decarboxylase (ODC) [donated by Dr. P. J. Blackshear, Duke University Medical School, Durham, NC]. The denatured cDNA probes were labeled with [32P] dATP by a random priming method (Multiprime DNA Labeling Systems, Amersham Biosciences). Prehybridization and hybridization solutions consisted of 50% formamide, 5X sodium chloride:sodium dihydrogen phosphate:EDTA acid disodium salt (SSPE), 5X Denhardt’s solution, 0.5% SDS, and 100 mg/L denatured salmon sperm DNA. The membranes were prehybridized for 3 h at 42°C. Hybridization was performed for 18 h at 42°C. The membranes were washed twice at room temperature in a solution containing 5X SSPE and 0.5% SDS, followed by washing twice at 37°C in a solution containing 1X SSPE and 0.5% SDS. The membranes were exposed to X-ray film (Kodak) with an intensifying screen at -70°C. The relative intensities of the autoradiograms were quantitated by densitometry. For a loading control, membranes were stripped and rehybridized with human 28S ribosomal RNA (American Type Culture Collection).
Statistical analysis. All statistical analyses were performed by SAS/STAT Version 6.11 (SAS Institute). Growth and lactation data were analyzed using one-way ANOVA with repeated measures. Gene expression, proliferation, and enzyme activity data were analyzed by 2-way ANOVA. If the F-statistic for the ANOVA was significant, means were further evaluated by independent t test. Differences were considered significant at P < 0.05.
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RESULTS AND DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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Multistep nutrition regimens imposed during peripuberty through gestation were shown to positively affect mammary tissue development and subsequent lactation performance (11–14). However, implementation of these innovative multistep models is rather involved. The present one-step CNR model was designed to induce compensatory growth during late gestation after energy restriction during early gestation. As expected, the CNR rats gained minimal weight during the restriction phase (early gestation); however, during the realimentation period (late gestation), they exhibited compensatory growth and attained a body weight (P = 0.427) and feed intake (P = 0.138) similar to that of the control rats by d 16 and 18 of gestation, respectively (Fig. 1). Body weight did not differ between the groups throughout lactation (data not shown).
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Changes in feeding intensity (energy density) can alter the secretion of one or more of the hormones that regulate mammary growth and differentiation during hormone-dependent stages of development as growth shifts from isometric to allometric (1). An increase in plasma growth hormone (GH) is typical for most animals when they consume energy-restricted diets. Decreased insulin, insulin-like growth factor-I (IGF-I), 3,5,3'-triiodothyronine, and thyroxine caused by lower energy influx likely reduce the synthesis of GH receptors and plasma levels of GH binding proteins; consequently, circulating plasma GH increases. During feed restriction, plasma IGF-I concentration decreases due to lower GH receptor availability (21). High circulating levels of GH during energy restriction improve fat mobilization, making more energy available to the cells. However, this change in the GH/IGF-I axis continues to prevail during compensatory growth. During refeeding and compensatory growth, plasma GH concentrations remain high. This situation probably further allows more nutrients to be used for growth processes (21). Heifers reared on our multistep compensatory growth model had higher GH levels than controls during the refeeding phase (22).
Lactation and pup performance.
There was no difference in litter size between the control and the CNR groups (12.61 ± 0.54 vs. 12.35 ± 0.69 pups). Although the pup weight on d 3 of lactation did not differ between the groups, the pup weight on d 18 of lactation was 10% higher (P = 0.13) in the CNR group than in the control group (Table 2). The estimated milk yield was also higher in the CNR group than in the control group. CNR dams produced 14% more (P < 0.05) milk than control dams (54.95 ± 3.63 vs. 48.20 ± 2.58 g/d). A study employing a similar, single stair-step nutrition model reported that CNR dams produced 17% more milk than control dams (4). These lactation data are further supported by a multistep regimen experiment in which the estimated milk yield was higher in the CNR group than in the control group during two consecutive lactation cycles (8.5%, first lactation; 15.6%, second lactation) (6).
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46% greater in mammary tissues from CNR rats during late gestation (P < 0.05) compared with those of the control group tissues (Table 3). This compensatory growth-directed increase in mammary cell proliferation corroborates findings from other studies with rats (3,4,6), heifers (9), and HC11 mammary cells in culture (23). It is possible that accelerated compensatory mammary growth induced during late gestation (i.e., the realimentation phase) may have altered the level and activities of genes regulating cell proliferation through changes in the endocrine status of the animal.
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73% from late gestation to EL; however, mammary cell proliferation in the compensatory group was still higher (26%) than that in the control group during EL (P = 0.07; Table 3). The number of mammary secretory cells determines milk yield. Further, proper nutritional status during gestation is critical to maximal mammary cell proliferation (1,2) because most epithelial cell proliferation occurs during late gestation (15). Therefore, the increase in mammary cell proliferation in the CNR group may be a reflection of compensatory growth induced during the realimentation phase, which was during the last 10 d of gestation. Ornithine decarboxylase. ODC is a key regulating enzyme in the biosynthesis of polyamines in mammalian cells and appears to play an important role in the control of a variety of biological processes including cellular metabolism, differentiation, membrane function, and proliferation (25). Nutritional status is an important factor in the regulation of ODC synthesis and cell proliferation. Elevated activities of ODC are normally present in rapidly developing tissues. This is true for the mammary gland during the phase of rapid growth and differentiation around parturition (25). The level of ODC mRNA was 64% (P < 0.05) higher in mammary tissues from the CNR group than in those from the control group during EL of the first lactation cycle (Fig. 2); ODC expression was 20% (P < 0.05) and 90% (P < 0.05) higher in mammary tissues from the CNR group than in those from the control group during both EL and LL of the second lactation cycle, respectively (Fig. 2).
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ß-Casein gene expression. Distinct steps of cellular differentiation take place during gestation and lactation. They are defined by the sequential activation of milk protein genes. The caseins are major milk proteins and are secreted only by differentiated mammary tissues. Induction and expression of milk proteins are controlled by complex multihormonal and enzymatic stimulation of transcriptional events, RNA processing, nucleocytoplasmic transport efficiency, stability of mRNA, and rate of translation (26). The extent to which casein is synthesized in the mammary gland depends on the accumulation of corresponding mRNA. The level of ß-casein mRNA in the CNR group was similar to that of the control group during EL and exceeded the level of control expression (17%; P < 0.05) during LL of the first lactation cycle (Fig. 3); during the second lactation cycle, ß-casein gene expression was 32% (P < 0.05) and 16% (P < 0.05) higher in tissues from the CNR group than in those from the control group during EL and LL, respectively (Fig. 3). The increased expression of this major milk protein gene is an indication of increased differentiation and functional activity in the mammary tissues of rats reared on the one-step gestational CNR. The CNR-mediated increase in ß-casein message in mammary tissues observed in the present study is in general agreement with our previous study (3) as well as those of others (14).
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After the peak of lactation, cell loss is largely responsible for the decline in milk yield, but activity per cell is maintained (1). Persistency of lactation may be affected by programmed cell death. Involution of the mammary gland is characterized by dramatic epithelial cell death and tissue remodeling (35) and has been described as a process exhibiting morphological features consistent with apoptotic cell death (36). Although mammary involution is normally induced by the weaning of the young, this process has already begun during LL in rodents (36). The synergistic interaction of nutritionally induced compensatory growth with developmentally related allometric growth may cause a cascade of upregulation of various genes affecting cellular activity including proliferation and differentiation. Increased cellular proliferation causes hyperplasia and hypertrophy for maximum parenchymal tissue growth in the mammary gland. Further, a physiologic consequence of compensatory mammary hyperplasia may be altered apoptotic signals, possibly through IGF-I, resulting in the suppression of apoptotic cell death.
The present study was intended to determine the effectiveness of a simplified one-step gestational compensatory growth nutrition model. To be an effective model, it is necessary to consider both the timing during which the regimen is imposed (i.e., hormonal state) and the extent and degree of energy modulation during both the restriction and realimentation phases. Overall, the effects of compensatory mammary growth induced only once during late gestation were similar to those of multistep models that encompass puberty to gestation. As with previous multistep models, the alteration of cellular functions and gene expression induced by the present one-step model manifested during the first lactation cycle and continued on into the second lactation cycle, suggesting that the enhanced functional activity of the mammary gland may be permanently maintained. The advantage of the one-step gestational model over multistep models is that it focuses on a well-defined and relatively short period of time, which greatly simplifies its implementation.
In addition to improving lactation potential by increasing proliferation and suppressing apoptosis in mammary epithelial cells, our CNR may offer opportunities in the development of a nutritional strategy for breast cancer prevention. The stimulation of rapid growth and fuller differentiation of mammary parenchymal tissue during gestation inhibits tumorigenesis (37). Fuller differentiation obtained with our CNR during gestation may increase resistance to mammary tumorigenesis. Our nutrition model may be useful in developing guidelines in nutrition counseling for pregnant women who have risk factors for developing breast cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by a grant (2001–35206-1007) from the U.S. Department of Agriculture-National Research Initiative.
3 Present address: Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
5 Abbreviations used: ABC, avidin:biotinylated peroxide complex; BrdU, bromodeoxyuridine; CNR, compensatory nutrition regimen; EL, early lactation; GH, growth hormone; IGF-I, insulin-like growth factor-I; LL, late lactation; ODC, ornithine decarboxylase; pNA, p-nitroaniline; SSPE, sodium chloride:sodium dihydrogen phosphate:EDTA acid disodium salt.
Manuscript received 30 July 2003. Initial review completed 28 September 2003. Revision accepted 31 December 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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1. Park, C. S. & Jacobson, N. L. (1993) The mammary gland and lactation. Swenson, M. J. Reece, W. O. eds. Dukes’ Physiology of Domestic Animals 1993:711-727 Cornell University Press Ithaca, NY. .
2. Wilde, C. J., Henderson, A. J. & Knight, C. H. (1986) Metabolic adaptations in goat mammary tissue during pregnancy and lactation. J. Reprod. Fertil. 76:289-298.
3. Park, C. S., Choi, Y. J., Keller, W. L. & Harrold, R. L. (1988) Effects of compensatory growth on milk protein gene expression and mammary differentiation. FASEB J. 2:2619-2624.[Abstract]
4. Kim, S. H., Moon, Y. S., Keller, W. L. & Park, C. S. (1998) Compensatory nutrition-directed mammary cell proliferation and lactation in rats. Br. J. Nutr. 79:177-183.[Medline]
5. Park, C. S., Baik, M. G., Keller, W. L. & Slanger, W. D. (1994) Dietary energy restriction-mediated growth and mammary development in rats. J. Anim. Sci. 72:2319-2324.[Abstract]
6. Moon, Y. S. & Park, C. S. (1999) Nutritionally- directed compensatory growth enhances mammary development and lactation potential in rats. J. Nutr. 129:1156-1160.
7. Crenshaw, J. D., Park, C. S., Swantek, P. M., Keller, W. L. & Zimprich, R. C. (1989) Lactation response of gilts to a phased feeding regimen designed to induce compensatory growth. J. Anim. Sci. 67(suppl. 2):107-108.
8. Park, C. S., Erickson, G. M., Choi, Y. J. & Marx, G. D. (1987) Effect of compensatory growth on regulation of growth and lactation: response of dairy heifers to a stair-step growth pattern. J. Anim. Sci. 64:1751-1758.
9. Park, C. S., Danielson, R. B., Kreft, B. S., Kim, S. H., Moon, Y. S. & Keller, W. L. (1998) Nutritionally directed compensatory growth and effects on lactation potential of developing heifers. J. Dairy Sci. 81:243-249.[Abstract]
10. Ford, J. A., Jr. & Park, C. S. (2001) Nutritionally directed compensatory growth enhances heifer development and lactation potential. J. Dairy Sci. 84:1669-1678.[Abstract]
11. Park, C. S. (1998) Heifer rearing for optimum lifetime production. Garnsworthy, P. C. Wiseman, J. eds. Recent Advances in Animal Nutrition 1998:165-180 Nottingham University Press Nottingham, UK. .
12. Barash, H., Bar-Meir, Y. & Bruckental, I. (1994) Effects of low-energy diet followed by a compensatory diet on growth, puberty and milk production in dairy heifers. Livest. Prod. Sci. 39:263-268.
13. Choi, Y. J., Han, I. K., Woo, J. H., Lee, H. J., Jang, K., Myung, K. H. & Kim, Y. S. (1997) Compensatory growth in dairy heifers: the effect of a compensatory growth pattern on growth rate and lactation performance. J. Dairy Sci. 80:519-524.[Abstract]
14. Choi, Y. J., Jang, K., Yim, D. S., Baik, M. G., Myung, K. H., Kim, Y. S., Lee, H. J., Kim, J. S. & Han, I. K. (1998) Effects of compensatory growth on the expression of milk protein gene and biochemical changes of the mammary gland in Holstein cows. J. Nutr. Biochem. 9:380-387.
15. Thordarson, G. & Talamantes, F. (1987) Role of the placenta on mammary gland development and function. Neville, M. C. Daniel, C. W. eds. The Mammary Gland Development, Regulation, and Function 1987:459-498 Plenum Press New York, NY. .
16. Paape, M. J. & Sinha, Y. N. (1971) Nucleic acid and collagen content of mammary glands between 30 and 80 days of age in normal and ovariectomized rats and during pregnancy. J. Dairy Sci. 54:1068-1074.
17. Reeves, P. G., Nielsen, F. H. & Fahey, G. C., Jr. (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J. Nutr. 123:1939-1951.
18. Sampson, D. A. & Jansen, G. R. (1984) Measurement of milk yield in the lactating rat from pup weight and weight gain. J. Pediatr. Gastroenterol. Nutr. 3:613-617.[Medline]
19. Weindruch, R. & Walford, R. L. (1988) Dietary restriction: effects on disease. Weindruch, R. Walford, R. L. eds. The Retardation of Aging and Disease by Dietary Restriction 1988:73-115 C. C. Thomas Publishers Springfield, IL. .
20. Newsholme, E. A. (1980) A possible metabolic basis for the control of body weight. N. Engl. J. Med. 302:400-405.[Medline]
21. Hornick, J. L., Van Eenaeme, C., Gerard, O., Dufrasne, I. & Istasse, L. (2000) Mechanisms of reduced and compensatory growth. Domest. Anim. Endocrinol. 19:121-132.[Medline]
22. Park, C. S., Baik, M. G., Keller, W. L., Berg, I. E. & Erickson, G. M. (1989) Role of compensatory growth in lactation: a stair-step nutrient regimen modulates differentiation and lactation of bovine mammary gland. Growth Dev. Aging 53:159-166.[Medline]
23. Schroeder, J. W., Keller, W. L. & Park, C. S. (2002) Glucose restriction and refeeding regimen alters proliferation and differentiation of HC11 mammary cells. In Vitro Cell. Dev. Biol. Anim. 38:135-136.[Medline]
24. Schmidt, G. H. (1971) Biology of Lactation 1971 W. H. Freeman and Company San Francisco, CA.
25. Russell, D. H. & McVicker, T. A. (1972) Polyamine biogenesis in the rat mammary gland during pregnancy and lactation. Biochem. J. 130:71-76.[Medline]
26. Guyette, W. A., Matusik, R. J. & Rosen, J. M. (1979) Prolactin-mediated transcriptional and post-transcriptional control of casein gene expression. Cell 17:1013-1023.[Medline]
27. Nakopoulou, L., Alexandrou, P., Stefanaki, K., Panayotopoulou, E., Lazaris, A. C. & Davaris, P. S. (2001) Immunohistochemical expression of caspase-3 as an adverse indicator of the clinical outcome in human breast cancer. Pathobiology 69:266-273.[Medline]
28. Wang, L., Ma, W., Markovich, R., Lee, W. L. & Wang, P. H. (1998) Insulin-like growth factor I modulates induction of apoptotic signaling in H9C2 cardiac muscle cells. Endocrinology 139:1354-1360.
29. Moon, Y. S. & Park, C. S. (2002) Effects of controlled compensatory growth on mammary gland development and lactation in rats. Asian-Australas. J. Anim. Sci. 15:1364-1370.
30. Kleinberg, D. L., Feldman, M. & Ruan, W. (2000) IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. J. Mammary Gland Biol. Neoplasia 5:7-17.[Medline]
31. Richert, M. M. & Wood, T. L. (1999) The insulin-like growth factors (IGF) and IGF type I receptor during postnatal growth of the murine mammary gland: sites of messenger ribonucleic acid expression and potential functions. Endocrinology 140:454-461.
32. Geier, A., Haimshon, M., Beery, R., Hemi, R. & Lunenfeld, B. (1992) Insulin-like growth factor-I inhibits cell death induced by cycloheximide in MCF-7 cells: a model system for analyzing control of cell death. In Vitro Cell. Dev. Biol. 28A:725-729.[Medline]
33. Hadsell, D. L., Greenberg, N. M., Fligger, J. M., Baumrucker, C. R. & Rosen, J. M. (1996) Targeted expression of des(1–3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression. Endocrinology 137:321-330.[Abstract]
34. Neuenschwander, S., Schwartz, A., Wood, T. L., Roberts, C. T., Jr., Hennighausen, L. & LeRoith, D. (1996) Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J. Clin. Invest. 97:2225-2232.[Medline]
35. Ossowski, L., Biegel, D. & Reich, E. (1979) Mammary plasminogen activator: correlation with involution, hormonal modulation and comparison between normal and neoplastic tissue. Cell 16:929-940.[Medline]
36. Walker, N. I., Bennett, R. E. & Kerr, J.F.R. (1989) Cell death by apoptosis during involution of the lactating breast in mice and rats. Am. J. Anat. 185:19-32.[Medline]
37. Russo, J. & Russo, I. H. (1995) The etiopathogenesis of breast cancer prevention. Cancer Lett 90:81-89.[Medline]
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