Top

Journal of Mammary Gland Biology and Neoplasia

Published in:

01-09-2019 | Obesity

Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution

Authors: Qiong A. Wang, Philipp E. Scherer

Published in: Journal of Mammary Gland Biology and Neoplasia | Issue 3/2019

Abstract

White adipocytes in the mammary gland stroma comprise the majority of the mammary gland mass. White adipocytes regulate numerous hormonal and metabolic processes and exhibit compositional and phenotypic plasticity. This plasticity is exemplified by the ability of mammary adipocytes to regress during lactation, when mammary epithelial cells expand to establish sufficient milk-producing alveoli. Upon weaning, the process reverses through mammary involution, during which adipocytes extensively regenerate, and alveolar epithelial cells disappear through cell death, returning the mammary gland to the non-lactating state. Despite intensive studies on the development and involution of the mammary alveolar epithelium, the fate of mammary adipocytes during pregnancy and lactation, and the origins of mammary adipocytes regenerated during mammary involution, is poorly understood. Here, we discuss the recent discoveries of the fate of mammary adipocytes during pregnancy and lactation in a number of different mouse models, and the lineage origin of mammary adipocytes regenerated during involution.

Landskroner-Eiger S, Park J, Israel D, Pollard JW, Scherer PE. Morphogenesis of the developing mammary gland: stage-dependent impact of adipocytes. Dev Biol. 2010;344(2):968–78. https://doi.org/10.1016/j.ydbio.2010.06.019.CrossRefPubMedPubMedCentral

Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. Eur J Clin Investig. 2011;121(6):2094–101. https://doi.org/10.1172/jci45887.CrossRef

Rosen Evan D, Spiegelman BM. What We Talk About When We Talk About Fat. Cell. 156(1):20–44. https://doi.org/10.1016/j.cell.2013.12.012.CrossRefPubMedPubMedCentral

Rutkowski JM, Stern JH, Scherer PE. The cell biology of fat expansion. J Cell Biol. 2015;208(5):501–12. https://doi.org/10.1083/jcb.201409063.CrossRefPubMedPubMedCentral

Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019. https://doi.org/10.1038/s41580-018-0093-z.CrossRefPubMed

Rillema JA. Development of the mammary gland and lactation. Trends Endocrinol Metab. 1994;5(4):149–54.CrossRefPubMed

Lund LR, Romer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, et al. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development. 1996;122(1):181–93.PubMedPubMedCentral

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 U S A. 1997;94(7):3425–30.CrossRefPubMedPubMedCentral

Richert MM, Schwertfeger KL, Ryder JW, Anderson SM. An atlas of mouse mammary gland development. J Mammary Gland Biol Neoplasia. 2000;5(2):227–41. https://doi.org/10.1023/A:1026499523505.CrossRefPubMed

10.

Eirew P, Stingl J, Raouf A, Turashvili G, Aparicio S, Emerman JT, et al. A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat Med. 2008;14(12):1384–9 http://www.nature.com/nm/journal/v14/n12/suppinfo/nm.1791_S1.html.CrossRefPubMed

11.

Tiede B, Kang Y. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res. 2011;21(2):245–57. https://doi.org/10.1038/cr.2011.11.CrossRefPubMedPubMedCentral

12.

Lloyd-Lewis B, Harris OB, Watson CJ, Davis FM. Mammary stem cells: premise, properties, and perspectives. Trends Cell Biol. 2017;27(8):556–67. https://doi.org/10.1016/j.tcb.2017.04.001.CrossRefPubMed

13.

Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479:189. https://doi.org/10.1038/nature10573 https://www.nature.com/articles/nature10573#supplementary-information.CrossRefPubMed

14.

Lafkas D, Rodilla V, Huyghe M, Mourao L, Kiaris H, Fre S. Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J Cell Biol. 2013;203(1):47–56. https://doi.org/10.1083/jcb.201307046.CrossRefPubMedPubMedCentral

15.

Chang THT, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res. 2014;16(1):R1. https://doi.org/10.1186/bcr3593.CrossRefPubMedPubMedCentral

16.

Prater MD, Petit V, Alasdair Russell I, Giraddi RR, Shehata M, Menon S, et al. Mammary stem cells have myoepithelial cell properties. Nat Cell Biol. 2014;16:942. https://doi.org/10.1038/ncb3025 https://www.nature.com/articles/ncb3025#supplementary-information.CrossRefPubMedPubMedCentral

17.

Rodilla V, Dasti A, Huyghe M, Lafkas D, Laurent C, Reyal F, et al. Luminal progenitors restrict their lineage potential during mammary gland development. PLoS Biol. 2015;13(2):e1002069. https://doi.org/10.1371/journal.pbio.1002069.CrossRefPubMedPubMedCentral

18.

Wuidart A, Ousset M, Rulands S, Simons BD, Van Keymeulen A, Blanpain C. Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells. Genes Dev. 2016;30(11):1261–77. https://doi.org/10.1101/gad.280057.116.CrossRefPubMedPubMedCentral

19.

Joshi PA, Waterhouse PD, Kasaian K, Fang H, Gulyaeva O, Sul HS, et al. PDGFRα+ stromal adipocyte progenitors transition into epithelial cells during lobulo-alveologenesis in the murine mammary gland. Nat Commun. 2019;10(1):1760. https://doi.org/10.1038/s41467-019-09748-z.CrossRefPubMedPubMedCentral

20.

Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8 http://www.nature.com/nature/journal/v439/n7072/suppinfo/nature04372_S1.html.CrossRefPubMed

21.

Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439(7079):993–7. https://doi.org/10.1038/nature04496.CrossRefPubMed

22.

van Amerongen R, Bowman Angela N, Nusse R. Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell. 2012;11(3):387–400. https://doi.org/10.1016/j.stem.2012.05.023.CrossRefPubMed

23.

Rios AC, Fu NY, Lindeman GJ, Visvader JE. In situ identification of bipotent stem cells in the mammary gland. Nature. 2014;506:322. https://doi.org/10.1038/nature12948 https://www.nature.com/articles/nature12948#supplementary-information.CrossRefPubMed

24.

Wang D, Cai C, Dong X, Yu QC, Zhang XO, Yang L, et al. Identification of multipotent mammary stem cells by protein C receptor expression. Nature. 2015;517(7532):81–4. https://doi.org/10.1038/nature13851.CrossRefPubMed

25.

Davis FM, Lloyd-Lewis B, Harris OB, Kozar S, Winton DJ, Muresan L, et al. Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny. Nat Commun. 2016;7:13053. https://doi.org/10.1038/ncomms13053 https://www.nature.com/articles/ncomms13053#supplementary-information.CrossRefPubMedPubMedCentral

26.

Morroni M, Giordano A, Zingaretti MC, Boiani R, De Matteis R, Kahn BB, et al. Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland. Proc Natl Acad Sci U S A. 2004;101(48):16801–6. https://doi.org/10.1073/pnas.0407647101.CrossRefPubMedPubMedCentral

27.

Prokesch A, Smorlesi A, Perugini J, Manieri M, Ciarmela P, Mondini E, et al. Molecular aspects of adipoepithelial transdifferentiation in mouse mammary gland. Stem Cells. 2014;32(10):2756–66. https://doi.org/10.1002/stem.1756.CrossRefPubMedPubMedCentral

28.

Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19(10):1338–44. https://doi.org/10.1038/nm.3324.CrossRefPubMedPubMedCentral

29.

Wang QA, Song A, Chen W, Schwalie PC, Zhang F, Vishvanath L, Jiang L, Ye R, Shao M, Tao C, Gupta RK, Deplancke B, Scherer PE. Reversible De-differentiation of Mature White Adipocytes into Preadipocyte-like Precursors during Lactation. Cell Metabolism. 2018;28(2):282–8.e3. https://doi.org/10.1016/j.cmet.2018.05.022.CrossRefPubMedPubMedCentral

30.

Zwick RK, Rudolph MC, Shook BA, Holtrup B, Roth E, Lei V, et al. Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation. Nat Commun. 2018;9(1):–3592. https://doi.org/10.1038/s41467-018-05911-0.

31.

Jena MK, Jaswal S, Kumar S, Mohanty AK. Molecular mechanism of mammary gland involution: An update. Dev Biol. 2019;445(2):145–55. https://doi.org/10.1016/j.ydbio.2018.11.002.CrossRefPubMed

32.

Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12(1):25–35. https://doi.org/10.1007/s10911-007-9035-7.CrossRefPubMed

33.

Jena MK, Jaswal S, Kumar S, Mohanty AK. Molecular mechanism of mammary gland involution: An update. Dev Biol. 2019;445(2):145–55. https://doi.org/10.1016/j.ydbio.2018.11.002.CrossRefPubMed

34.

Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150(6):1223–34.CrossRefPubMedPubMedCentral

35.

Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature. 2013;503(7475):218.CrossRefPubMedPubMedCentral

36.

Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266–78 Epub 1995/09/15.CrossRefPubMed

37.

Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 1998;95(9):5076–81.CrossRefPubMedPubMedCentral

38.

Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia. 2002;7(1):49–66.CrossRefPubMed

39.

Kelly PA, Bachelot A, Kedzia C, Hennighausen L, Ormandy CJ, Kopchick JJ, et al. The role of prolactin and growth hormone in mammary gland development. Mol Cell Endocrinol. 2002;197(1–2):127–31.CrossRefPubMed

40.

Clegg RA. Lipoprotein lipase. Localization on plasma membrane fragments from lactating rat mammary tissue. Biochim Biophys Acta. 1981;664(2):397–408. https://doi.org/10.1016/0005-2760(81)90062-x.CrossRefPubMed

41.

Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of Obesity Among Adults and Youth: United States, 2015-2016. NCHS Data Brief. 2017;(288):1–8.

42.

Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1–2):20–44. https://doi.org/10.1016/j.cell.2013.12.012.CrossRefPubMedPubMedCentral

43.

Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov. 2016;15(9):639–60. https://doi.org/10.1038/nrd.2016.75.CrossRefPubMed

44.

Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest. 2017;127(1):74–82. https://doi.org/10.1172/JCI88883.CrossRefPubMedPubMedCentral

45.

Hilson JA, Rasmussen KM, Kjolhede CL. High prepregnant body mass index is associated with poor lactation outcomes among white, rural women independent of psychosocial and demographic correlates. Journal of human lactation : official journal of International Lactation Consultant Association. 2004;20(1):18–29. https://doi.org/10.1177/0890334403261345.CrossRef

46.

Rasmussen KM. Association of Maternal Obesity before Conception with poor lactation performance. Annu Rev Nutr. 2007;27(1):103–21. https://doi.org/10.1146/annurev.nutr.27.061406.093738.CrossRefPubMed

47.

Jevitt C, Hernandez I, Groer M. Lactation complicated by overweight and obesity: supporting the mother and newborn. J Midwifery Womens Health. 2007;52(6):606–13. https://doi.org/10.1016/j.jmwh.2007.04.006.CrossRefPubMed

48.

Rasmussen KM. Association of maternal obesity before conception with poor lactation performance. Annu Rev Nutr. 2007;27:103–21.CrossRefPubMed

49.

Chu SY, Bachman DJ, Callaghan WM, Whitlock EP, Dietz PM, Berg CJ, et al. Association between obesity during pregnancy and increased use of health care. N Engl J Med. 2008;358(14):1444–53. https://doi.org/10.1056/NEJMoa0706786.CrossRefPubMed

50.

Davies GA, Maxwell C, McLeod L, Gagnon R, Basso M, Bos H, et al. Obesity in pregnancy. Int J Gynecol Obstet. 2010;110(2):167–73.CrossRef

51.

Riddle SW, Nommsen-Rivers LA. A case control study of diabetes during pregnancy and low milk supply. Breastfeed Med. 2016;11(2):80–5.CrossRefPubMedPubMedCentral

52.

Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356. https://doi.org/10.1136/bmj.j1.

53.

Stuebe AM, Rich-Edwards JW, Willett WC, Manson JE, Michels KB. Duration of lactation and incidence of type 2 diabetes. Jama. 2005;294(20):2601–10. https://doi.org/10.1001/jama.294.20.2601.CrossRefPubMed

54.

Schwarz EB, Brown JS, Creasman JM, Stuebe A, McClure CK, Van Den Eeden SK, Thom D. Lactation and maternal risk of type 2 diabetes: a population-based study. Am J Med. 2010;123(9):863. e1-. e6.CrossRefPubMedCentral

55.

Ziegler A-G, Wallner M, Kaiser I, Rossbauer M, Harsunen MH, Lachmann L, et al. Long-term protective effect of lactation on the development of type 2 diabetes in women with recent gestational diabetes mellitus. Diabetes. 2012;61(12):3167–71.CrossRefPubMedPubMedCentral

56.

Arenz S, Ruckerl R, Koletzko B, von Kries R. Breast-feeding and childhood obesity--a systematic review. Int J Obes Relat Metab Disord. 2004;28(10):1247–56. https://doi.org/10.1038/sj.ijo.0802758.CrossRefPubMed

57.

Organization WH. Exclusive Breastfeeding to Reduce the Risk of Childhood Overweight and Obesity 2004.

58.

Martin RM, Gunnell D, Davey SG. Breastfeeding in infancy and blood pressure in later life: systematic review and meta-analysis. Am J Epidemiol. 2005;161(1):15–26.CrossRefPubMed

59.

Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics. 2005;115(5):1367–77.CrossRefPubMed

60.

Owen CG, Martin RM, Whincup PH, Davey-Smith G, Gillman MW, Cook DG. The effect of breastfeeding on mean body mass index throughout life: a quantitative review of published and unpublished observational evidence. Am J Clin Nutr. 2005;82(6):1298–307.CrossRefPubMed

61.

Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr. 2006;84(5):1043–54.CrossRefPubMed

62.

Quigley MA. Re: "duration of breastfeeding and risk of overweight: a meta-analysis". Am J Epidemiol. 2006;163(9):870–2; author reply 2-3. https://doi.org/10.1093/aje/kwj134.CrossRefPubMed

63.

Owen CG, Whincup PH, Kaye SJ, Martin RM, Davey Smith G, Cook DG, et al. Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence. Am J Clin Nutr. 2008;88(2):305–14.CrossRefPubMed

64.

Savino F, Liguori SA, Fissore MF, Oggero R. Breast milk hormones and their protective effect on obesity. Int J Pediatr Endocrinol. 2009;2009(1):327505.CrossRefPubMedPubMedCentral

65.

Bernardo H, Cesar V, Organization, WH. Long-term effects of breastfeeding: a systematic review 2013.

66.

Hovey RC, Aimo L. Diverse and active roles for adipocytes during mammary gland growth and function. J Mammary Gland Biol Neoplasia. 2010;15(3):279–90.CrossRefPubMedPubMedCentral

67.

Schedin P, Keely PJ. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol. 2011;3(1):a003228.CrossRefPubMedPubMedCentral

68.

Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011;479(7372):189.CrossRefPubMed

69.

Macias H, Hinck L. Mammary gland development. Wiley Interdiscip Rev Dev Biol. 2012;1(4):533–57.CrossRefPubMedPubMedCentral

70.

Inman JL, Robertson C, Mott JD, Bissell MJ. Mammary gland development: cell fate specification, stem cells and the microenvironment. Development. 2015;142(6):1028–42.CrossRefPubMed

71.

Akers RM. Lactation and the mammary gland: John Wiley & Sons; 2016.

72.

Flint DJ, Travers MT, Barber MC, Binart N, Kelly PA. Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland. Am J Physiol Endocrinol Metab. 2005;288(6):E1179–E87. https://doi.org/10.1152/ajpendo.00433.2004.CrossRefPubMed

73.

Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331(1):5–9. https://doi.org/10.1056/nejm199407073310102.CrossRefPubMed

74.

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

75.

Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol. 2009;27(1):45–51.CrossRefPubMed

76.

Park J, Scherer PE. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Invest. 2012;122(11):4243–56. https://doi.org/10.1172/JCI63930.CrossRefPubMedPubMedCentral

77.

Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, et al. JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab. 2018;27(6):1357. https://doi.org/10.1016/j.cmet.2018.04.018.CrossRefPubMedPubMedCentral

78.

Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer--mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10(8):455–65. https://doi.org/10.1038/nrendo.2014.94.CrossRefPubMedPubMedCentral

Title: Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution
Authors: Qiong A. Wang
Philipp E. Scherer
Publication date: 01-09-2019
Publisher: Springer US
Keywords: Obesity
Obesity
Breast Cancer
Lactation
Breast Cancer
Published in: Journal of Mammary Gland Biology and Neoplasia / Issue 3/2019
Print ISSN: 1083-3021
Electronic ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-019-09434-2

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 3/2019

The Eleventh ENBDC Workshop: Advances in Technology Help to Unveil Mechanisms of Mammary Gland Development and Cancerogenesis

BRCA1 Attenuates Progesterone Effects on Proliferation and NFκB Activation in Normal Human Mammary Epithelial Cells

How to Choose a Mouse Model of Breast Cancer, a Genomic Perspective

GATA3 Truncating Mutations Promote Cistromic Re-Programming In Vitro, but Not Mammary Tumor Formation in Mice

Emerging Role of SOX Proteins in Breast Cancer Development and Maintenance

The Milk Protein Alpha-Casein Suppresses Triple Negative Breast Cancer Stem Cell Activity Via STAT and HIF-1alpha Signalling Pathways in Breast Cancer Cells and Fibroblasts

Keynote webinar | Spotlight on antibody–drug conjugates in cancer