Top

Journal of Mammary Gland Biology and Neoplasia

Published in:

Open Access 01-06-2009

Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies

Authors: Derek C. Radisky, Lynn C. Hartmann

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 2/2009

Abstract

Postlactational involution is the process following weaning during which the mammary gland undergoes massive cell death and tissue remodeling as it returns to the pre-pregnant state. Lobular involution is the process by which the breast epithelial tissue is gradually lost with aging of the mammary gland. While postlactational involution and lobular involution are distinct processes, recent studies have indicated that both are related to breast cancer development. Experiments using a variety of rodent models, as well as observations in human populations, suggest that deregulation of postlactational involution may act to facilitate tumor formation. By contrast, new human studies show that completion of lobular involution protects against subsequent breast cancer incidence.

Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004;6(1):1–11.PubMed

Watson CJ. Post-lactational mammary gland regression: molecular basis and implications for breast cancer. Expert Rev Mol Med. 2006;8(32):1–15. doi:10.1017/S1462399406000196.PubMed

Hutson SW, Cowen PN, Bird CC. Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. J Clin Pathol. 1985;38(3):281–7. doi:10.1136/jcp.38.3.281.PubMed

Milanese TR, Hartmann LC, Sellers TA, Frost MH, Vierkant RA, Maloney SD, et al. Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst. 2006;98(22):1600–7.PubMed

Watson CJ. Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res. 2006;8(2):203. doi:10.1186/bcr1401.PubMed

Marti A, Feng Z, Altermatt HJ, Jaggi R. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol. 1997;73(2):158–65.PubMed

Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, et al. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci USA. 1997;94(7):3425–30. doi:10.1073/pnas.94.7.3425.PubMed

Baxter FO, Neoh K, Tevendale MC. The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia. 2007;12(1):3–13. doi:10.1007/s10911-007-9033-9.PubMed

Feng Z, Marti A, Jehn B, Altermatt HJ, Chicaiza G, Jaggi R. Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol. 1995;131(4):1095–103. doi:10.1083/jcb.131.4.1095.PubMed

10.

Green KA, Lund LR. ECM degrading proteases and tissue remodelling in the mammary gland. Bioessays. 2005;27(9):894–903. doi:10.1002/bies.20281.PubMed

11.

Almholt K, Green KA, Juncker-Jensen A, Nielsen BS, Lund LR, Romer J. Extracellular proteolysis in transgenic mouse models of breast cancer. J Mammary Gland Biol Neoplasia. 2007;12(1):83–97. doi:10.1007/s10911-007-9040-x.PubMed

12.

Clarkson RW, Watson CJ. Microarray analysis of the involution switch. J Mammary Gland Biol Neoplasia. 2003;8(3):309–19. doi:10.1023/B:JOMG.0000010031.53310.92.PubMed

13.

Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res. 2004;6(2):R92–109. doi:10.1186/bcr754.PubMed

14.

Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6(2):R75–91. doi:10.1186/bcr753.PubMed

15.

Schedin P, O’Brien J, Rudolph M, Stein T, Borges V. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J Mammary Gland Biol Neoplasia. 2007;12(1):71–82. doi:10.1007/s10911-007-9039-3.PubMed

16.

van Kempen LC, Ruiter DJ, van Muijen GN, Coussens LM. The tumor microenvironment: a critical determinant of neoplastic evolution. Eur J Cell Biol. 2003;82(11):539–48. doi:10.1078/0171-9335-00346.PubMed

17.

Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6(4):281–91. doi:10.1038/nrc1839.PubMed

18.

Bemis LT, Schedin P. Reproductive state of rat mammary gland stroma modulates human breast cancer cell migration and invasion. Cancer Res. 2000;60(13):3414–8.PubMed

19.

McDaniel SM, Rumer KK, Biroc SL, Metz RP, Singh M, Porter W, et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol. 2006;168(2):608–20. doi:10.2353/ajpath.2006.050677.PubMed

20.

Schedin P, Mitrenga T, McDaniel S, Kaeck M. Mammary ECM composition and function are altered by reproductive state. Mol Carcinog. 2004;41(4):207–20. doi:10.1002/mc.20058.PubMed

21.

Song J, Sapi E, Brown W, Nilsen J, Tartaro K, Kacinski BM, et al. Roles of Fas and Fas ligand during mammary gland remodeling. J Clin Invest. 2000;106(10):1209–20. doi:10.1172/JCI10411.PubMed

22.

Zhao L, Melenhorst JJ, Hennighausen L. Loss of interleukin 6 results in delayed mammary gland involution: a possible role for mitogen-activated protein kinase and not signal transducer and activator of transcription 3. Mol Endocrinol. 2002;16(12):2902–12. doi:10.1210/me.2001-0330.PubMed

23.

Sohn BH, Moon HB, Kim TY, Kang HS, Bae YS, Lee KK, et al. Interleukin-10 up-regulates tumour-necrosis-factor-alpha-related apoptosis-inducing ligand (TRAIL) gene expression in mammary epithelial cells at the involution stage. Biochem J. 2001;360(Pt 1):31–8. doi:10.1042/0264-6021:3600031.PubMed

24.

Kritikou EA, Sharkey A, Abell K, Came PJ, Anderson E, Clarkson RW, et al. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development. 2003;130(15):3459–68. doi:10.1242/dev.00578.PubMed

25.

Nguyen AV, Pollard JW. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development. 2000;127(14):3107–18.PubMed

26.

Jager R, Herzer U, Schenkel J, Weiher H. Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene. 1997;15(15):1787–95. doi:10.1038/sj.onc.1201353.PubMed

27.

Schorr K, Li M, Bar-Peled U, Lewis A, Heredia A, Lewis B, et al. Gain of Bcl-2 is more potent than bax loss in regulating mammary epithelial cell survival in vivo. Cancer Res. 1999;59(11):2541–5.PubMed

28.

Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y, et al. Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell. 2005;16(12):5528–37. doi:10.1091/mbc.E05-02-0128.PubMed

29.

Hanayama R, Nagata S. Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci USA. 2005;102(46):16886–91. doi:10.1073/pnas.0508599102.PubMed

30.

Talhouk RS, Bissell MJ, Werb Z. Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. J Cell Biol. 1992;118(5):1271–82. doi:10.1083/jcb.118.5.1271.PubMed

31.

Talhouk RS, Chin JR, Unemori EN, Werb Z, Bissell MJ. Proteinases of the mammary gland: developmental regulation in vivo and vectorial secretion in culture. Development. 1991;112(2):439–49.PubMed

32.

Alexander CM, Howard EW, Bissell MJ, Werb Z. Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J Cell Biol. 1996;135(6 Pt 1):1669–77. doi:10.1083/jcb.135.6.1669.PubMed

33.

Alexander CM, Selvarajan S, Mudgett J, Werb Z. Stromelysin-1 regulates adipogenesis during mammary gland involution. J Cell Biol. 2001;152(4):693–703. doi:10.1083/jcb.152.4.693.PubMed

34.

Lund LR, Bjorn SF, Sternlicht MD, Nielsen BS, Solberg H, Usher PA, et al. Lactational competence and involution of the mouse mammary gland require plasminogen. Development. 2000;127(20):4481–92.PubMed

35.

Sympson CJ, Talhouk RS, Alexander CM, Chin JR, Clift SM, Bissell MJ, et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol. 1994;125(3):681–93. doi:10.1083/jcb.125.3.681.PubMed

36.

Green KA, Nielsen BS, Castellino FJ, Romer J, Lund LR. Lack of plasminogen leads to milk stasis and premature mammary gland involution during lactation. Dev Biol. 2006;299(1):164–75. doi:10.1016/j.ydbio.2006.07.021.PubMed

37.

Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988;54(1):105–15. doi:10.1016/0092-8674(88)90184-5.PubMed

38.

Lazar H, Baltzer A, Gimmi C, Marti A, Jaggi R. Over-expression of erbB-2/neu is paralleled by inhibition of mouse-mammary-epithelial-cell differentiation and developmental apoptosis. Int J Cancer. 2000;85(4):578–83. doi:10.1002/(SICI)1097-0215(20000215)85:4<578::AID-IJC21>3.0.CO;2-S.PubMed

39.

Hutchinson J, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol Cell Biol. 2001;21(6):2203–12. doi:10.1128/MCB.21.6.2203-2212.2001.PubMed

40.

Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res. 2004;64(9):3171–8. doi:10.1158/0008-5472.CAN-03-3465.PubMed

41.

Ackler S, Ahmad S, Tobias C, Johnson MD, Glazer RI. Delayed mammary gland involution in MMTV-AKT1 transgenic mice. Oncogene. 2002;21(2):198–206. doi:10.1038/sj.onc.1205052.PubMed

42.

Schwertfeger KL, Richert MM, Anderson SM. Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol. 2001;15(6):867–81. doi:10.1210/me.15.6.867.PubMed

43.

Shibata MA, Liu ML, Knudson MC, Shibata E, Yoshidome K, Bandey T, et al. Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice: reduction in protective apoptotic response at the preneoplastic stage. EMBO J. 1999;18(10):2692–701. doi:10.1093/emboj/18.10.2692.PubMed

44.

Furth PA, Bar-Peled U, Li M, Lewis A, Laucirica R, Jager R, et al. Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model. Oncogene. 1999;18(47):6589–96. doi:10.1038/sj.onc.1203073.PubMed

45.

Radisky DC, Bissell MJ. Matrix metalloproteinase-induced genomic instability. Curr Opin Genet Dev. 2006;16(1):45–50. doi:10.1016/j.gde.2005.12.011.PubMed

46.

Sun Y, Strizzi L, Raafat A, Hirota M, Bianco C, Feigenbaum L, et al. Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis. Am J Pathol. 2005;167(2):585–97.PubMed

47.

Wechselberger C, Strizzi L, Kenney N, Hirota M, Sun Y, Ebert A, et al. Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma. Oncogene. 2005;24(25):4094–105.PubMed

48.

Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell. 1999;98(2):137–46. doi:10.1016/S0092-8674(00)81009-0.PubMed

49.

Sympson CJ, Bissell MJ, Werb Z. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1. Semin Cancer Biol. 1995;6(3):159–63. doi:10.1006/scbi.1995.0022.PubMed

50.

Stewart TA, Pattengale PK, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984;38(3):627–37. doi:10.1016/0092-8674(84)90257-5.PubMed

51.

Boudreau N, Werb Z, Bissell MJ. Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle. Proc Natl Acad Sci USA. 1996;93(8):3509–13. doi:10.1073/pnas.93.8.3509.PubMed

52.

Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001;1(4):467–75. doi:10.1016/S1534-5807(01)00064-8.PubMed

53.

Russo J, Russo IH. Development of the human breast. Maturitas. 2004;49(1):2–15. doi:10.1016/j.maturitas.2004.04.011.PubMed

54.

Vorrherr H. The breast: morphology, physiology, and lactation. New York: Academic; 1974.

55.

Howard BA, Gusterson BA. Human breast development. J Mammary Gland Biol Neoplasia. 2000;5(2):119–37. doi:10.1023/A:1026487120779.PubMed

56.

Geschickter C. Diseases of the breast. Philadelphia: J.B. Lipincott Co; 1945.

57.

Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005;353(3):229–37. doi:10.1056/NEJMoa044383.PubMed

58.

Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst. 1975;55(2):231–73.PubMed

59.

Henson DE, Tarone RE, Nsouli H. Lobular involution: the physiological prevention of breast cancer. J Natl Cancer Inst. 2006;98(22):1589–90.PubMedCrossRef

60.

Baer HJ, Collins LC, Connolly JL, Colditz GA, Schnitt SJ, Tamimi RM. Lobule type and subsequent breast cancer risk: Results from the Nurses’ Health Studies. Cancer. 2009;115(7):1404–11. doi:10.1002/cncr.24167.PubMed

61.

Maroulakou IG, Oemler W, Naber SP, Klebba I, Kuperwasser C, Tsichlis PN. Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J Cell Physiol. 2008;217(2):468–77. doi:10.1002/jcp.21518.PubMed

62.

Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 2007;67(1):167–77. doi:10.1158/0008-5472.CAN-06-3782.PubMed

63.

Chang MY, Boulden J, Sutanto-Ward E, Duhadaway JB, Soler AP, Muller AJ, et al. Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression. Cancer Res. 2007;67(1):100–7. doi:10.1158/0008-5472.CAN-06-2742.PubMed

64.

Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006;66(9):4672–80. doi:10.1158/0008-5472.CAN-05-2909.PubMed

65.

Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P. Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol. 2001;153(3):555–68. doi:10.1083/jcb.153.3.555.PubMed

66.

Ma ZQ, Chua SS, DeMayo FJ, Tsai SY. Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B. Oncogene. 1999;18(32):4564–76. doi:10.1038/sj.onc.1202809.PubMed

67.

Yao Y, Slosberg ED, Wang L, Hibshoosh H, Zhang YJ, Xing WQ, et al. Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice. Oncogene. 1999;18(37):5159–66. doi:10.1038/sj.onc.1202908.PubMed

68.

Thangaraju M, Rudelius M, Bierie B, Raffeld M, Sharan S, Hennighausen L, et al. C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development. 2005;132(21):4675–85. doi:10.1242/dev.02050.PubMed

69.

Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem. 2001;276(21):18563–9. doi:10.1074/jbc.M010787200.PubMed

70.

Kirma N, Luthra R, Jones J, Liu YG, Nair HB, Mandava U, et al. Overexpression of the colony-stimulating factor (CSF-1) and/or its receptor c-fms in mammary glands of transgenic mice results in hyperplasia and tumor formation. Cancer Res. 2004;64(12):4162–70. doi:10.1158/0008-5472.CAN-03-2971.PubMed

71.

Brandt R, Eisenbrandt R, Leenders F, Zschiesche W, Binas B, Juergensen C, et al. Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation. Oncogene. 2000;19(17):2129–37. doi:10.1038/sj.onc.1203520.PubMed

72.

Marozkina NV, Stiefel SM, Frierson HF Jr, Parsons SJ. MMTV-EGF receptor transgene promotes preneoplastic conversion of multiple steroid hormone-responsive tissues. J Cell Biochem. 2008;103(6):2010–8. doi:10.1002/jcb.21591.PubMed

73.

Munarini N, Jager R, Abderhalden S, Zuercher G, Rohrbach V, Loercher S, et al. Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase. J Cell Sci. 2002;115(Pt 1):25–37.PubMed

74.

Morini M, Astigiano S, Mora M, Ricotta C, Ferrari N, Mantero S, et al. Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4. Oncogene. 2000;19(52):6007–14. doi:10.1038/sj.onc.1204011.PubMed

75.

Zhao L, Hart S, Cheng J, Melenhorst JJ, Bierie B, Ernst M, et al. Mammary gland remodeling depends on gp130 signaling through Stat3 and MAPK. J Biol Chem. 2004;279(42):44093–100. doi:10.1074/jbc.M313131200.PubMed

76.

Hadsell DL, Greenberg NM, Fligger JM, Baumrucker CR, Rosen JM. 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. 1996;137(1):321–30. doi:10.1210/en.137.1.321.PubMed

77.

Hadsell DL, Torres DT, Lawrence NA, George J, Parlow AF, Lee AV, et al. Overexpression of des(1–3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation. Biol Reprod. 2005;73(6):1116–25. doi:10.1095/biolreprod.105.043992.PubMed

78.

Neuenschwander S, Schwartz A, Wood TL, Roberts CT Jr, Hennighausen L, LeRoith D. Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J Clin Invest. 1996;97(10):2225–32. doi:10.1172/JCI118663.PubMed

79.

Hadsell DL, Murphy KL, Bonnette SG, Reece N, Laucirica R, Rosen JM. Cooperative interaction between mutant p53 and des(1–3) IGF-I accelerates mammary tumorigenesis. Oncogene. 2000;19(7):889–98. doi:10.1038/sj.onc.1203386.PubMed

80.

Moorehead RA, Fata JE, Johnson MB, Khokha R. Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice. Cell Death Differ. 2001;8(1):16–29. doi:10.1038/sj.cdd.4400762.PubMed

81.

Carboni JM, Lee AV, Hadsell DL, Rowley BR, Lee FY, Bol DK, et al. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer Res. 2005;65(9):3781–7. doi:10.1158/0008-5472.CAN-04-4602.PubMed

82.

Baxter FO, Came PJ, Abell K, Kedjouar B, Huth M, Rajewsky K, et al. IKKbeta/2 induces TWEAK and apoptosis in mammary epithelial cells. Development. 2006;133(17):3485–94. doi:10.1242/dev.02502.PubMed

83.

Wagner KU, Krempler A, Triplett AA, Qi Y, George NM, Zhu J, et al. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol. 2004;24(12):5510–20. doi:10.1128/MCB.24.12.5510-5520.2004.PubMed

84.

Bagheri-Yarmand R, Talukder AH, Wang RA, Vadlamudi RK, Kumar R. Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis. Development. 2004;131(14):3469–79. doi:10.1242/dev.01213.PubMed

85.

Schroeder JA, Masri AA, Adriance MC, Tessier JC, Kotlarczyk KL, Thompson MC, et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene. 2004;23(34):5739–47. doi:10.1038/sj.onc.1207713.PubMed

86.

Toyo-oka K, Bowen TJ, Hirotsune S, Li Z, Jain S, Ota S, et al. Mnt-deficient mammary glands exhibit impaired involution and tumors with characteristics of myc overexpression. Cancer Res. 2006;66(11):5565–73. doi:10.1158/0008-5472.CAN-05-2683.PubMed

87.

Hurlin PJ, Zhou ZQ, Toyo-oka K, Ota S, Walker WL, Hirotsune S, et al. Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis. EMBO J. 2003;22(18):4584–96. doi:10.1093/emboj/cdg442.PubMed

88.

Hu C, Dievart A, Lupien M, Calvo E, Tremblay G, Jolicoeur P. Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors. Am J Pathol. 2006;168(3):973–90. doi:10.2353/ajpath.2006.050416.PubMed

89.

Kiaris H, Politi K, Grimm LM, Szabolcs M, Fisher P, Efstratiadis A, et al. Modulation of notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. Am J Pathol. 2004;165(2):695–705.PubMed

90.

Jerry DJ, Kuperwasser C, Downing SR, Pinkas J, He C, Dickinson E, et al. Delayed involution of the mammary epithelium in BALB/c-p53null mice. Oncogene. 1998;17(18):2305–12. doi:10.1038/sj.onc.1202157.PubMed

91.

Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, Medina D, et al. Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome. Am J Pathol. 2000;157(6):2151–9.PubMed

92.

Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development. 2002;129(17):4159–70.PubMed

93.

Gonzalez-Suarez E, Branstetter D, Armstrong A, Dinh H, Blumberg H, Dougall WC. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol Cell Biol. 2007;27(4):1442–54. doi:10.1128/MCB.01298-06.PubMed

94.

Chapman RS, Lourenco P, Tonner E, Flint D, Selbert S, Takeda K, et al. The role of Stat3 in apoptosis and mammary gland involution. Conditional deletion of Stat3. Adv Exp Med Biol. 2000;480:129–38. doi:10.1007/0-306-46832-8_16.PubMed

95.

Humphreys RC, Bierie B, Zhao L, Raz R, Levy D, Hennighausen L. Deletion of Stat3 blocks mammary gland involution and extends functional competence of the secretory epithelium in the absence of lactogenic stimuli. Endocrinology. 2002;143(9):3641–50. doi:10.1210/en.2002-220224.PubMed

96.

Bierie B, Gorska AE, Stover DG, Moses HL. TGF-beta promotes cell death and suppresses lactation during the second stage of mammary involution. J Cell Physiol. 2009;219(1):57–68. doi:10.1002/jcp.21646.PubMed

97.

Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL. Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol. 2003;163(4):1539–49.PubMed

98.

Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M, et al. Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res. 2008;68(6):1809–19. doi:10.1158/0008-5472.CAN-07-5597.PubMed

99.

Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR, et al. Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res. 2005;65(6):2296–302. doi:10.1158/0008-5472.CAN-04-3272.PubMed

100.

Sandgren EP, Schroeder JA, Qui TH, Palmiter RD, Brinster RL, Lee DC. Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res. 1995;55(17):3915–27.PubMed

101.

Zinser GM, Welsh J. Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol. 2004;18(9):2208–23. doi:10.1210/me.2003-0469.PubMed

102.

Zinser GM, Suckow M, Welsh J. Vitamin D receptor (VDR) ablation alters carcinogen-induced tumorigenesis in mammary gland, epidermis and lymphoid tissues. J Steroid Biochem Mol Biol. 2005;97(1–2):153–64. doi:10.1016/j.jsbmb.2005.06.024.PubMed

103.

Zinser GM, Welsh J. Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. Carcinogenesis. 2004;25(12):2361–72. doi:10.1093/carcin/bgh271.PubMed

104.

Bagheri-Yarmand R, Vadlamudi RK, Kumar R. Activating transcription factor 4 overexpression inhibits proliferation and differentiation of mammary epithelium resulting in impaired lactation and accelerated involution. J Biol Chem. 2003;278(19):17421–9. doi:10.1074/jbc.M300761200.PubMed

105.

Faraldo MM, Deugnier MA, Tlouzeau S, Thiery JP, Glukhova MA. Perturbation of beta1-integrin function in involuting mammary gland results in premature dedifferentiation of secretory epithelial cells. Mol Biol Cell. 2002;13(10):3521–31. doi:10.1091/mbc.E02-02-0086.PubMed

106.

White DE, Kurpios NA, Zuo D, Hassell JA, Blaess S, Mueller U, et al. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004;6(2):159–70. doi:10.1016/j.ccr.2004.06.025.PubMed

107.

Walton KD, Wagner KU, Rucker EB 3rd, Shillingford JM, Miyoshi K, Hennighausen L. Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation. Mech Dev. 2001;109(2):281–93. doi:10.1016/S0925-4773(01)00549-4.PubMed

108.

Chapman RS, Duff EK, Lourenco PC, Tonner E, Flint DJ, Clarke AR, et al. A novel role for IRF-1 as a suppressor of apoptosis. Oncogene. 2000;19(54):6386–91. doi:10.1038/sj.onc.1204016.PubMed

109.

Schaapveld RQ, Schepens JT, Robinson GW, Attema J, Oerlemans FT, Fransen JA, et al. Impaired mammary gland development and function in mice lacking LAR receptor-like tyrosine phosphatase activity. Dev Biol. 1997;188(1):134–46. doi:10.1006/dbio.1997.8630.PubMed

110.

Robinson GW, Pacher-Zavisin M, Zhu BM, Yoshimura A, Hennighausen L. Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis. Dev Dyn. 2007;236(3):654–61. doi:10.1002/dvdy.21058.PubMed

111.

Humphreys RC, Hennighausen L. Signal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis. Cell Growth Differ. 1999;10(10):685–94.PubMed

112.

Ren S, Cai HR, Li M, Furth PA. Loss of Stat5a delays mammary cancer progression in a mouse model. Oncogene. 2002;21(27):4335–9. doi:10.1038/sj.onc.1205484.PubMed

113.

Fata JE, Leco KJ, Voura EB, Yu HY, Waterhouse P, Murphy G, et al. Accelerated apoptosis in the Timp-3-deficient mammary gland. J Clin Invest. 2001;108(6):831–41.PubMed

Title: Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies
Authors: Derek C. Radisky
Lynn C. Hartmann
Publication date: 01-06-2009
Publisher: Springer US
Published in: Journal of Mammary Gland Biology and Neoplasia / Issue 2/2009
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-009-9123-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2009

Stat3 and the Inflammation/Acute Phase Response in Involution and Breast Cancer

Macrophages in Breast Cancer: Do Involution Macrophages Account for the Poor Prognosis of Pregnancy-Associated Breast Cancer?

Pregnancy and Breast Cancer: when They Collide

Preface

A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis

A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer