Abstract
The growth and morphogenesis of mammaryparenchyma varies substantially between species and isregulated by an array of systemic and local factors.Central to this regulation is the mammary fat pad, amatrix of adipose and connective tissue capable ofmediating hormone action and synthesizing an array ofgrowth regulatory molecules. In this article wehighlight differences between the morphologicaldevelopment of the mammary parenchyma in rodents, humans,and ruminant dairy animals, placing emphasis ondifferences in the cellular composition and structure ofthe mammary fat pad. While a great deal remains to be understood about the ability of stroma tolocally regulate mammary development, the significanceof its contribution is becoming increasingly apparent.The actions of several steroid and peptide hormones appear to be mediated by an array of growthfactors, proteases and extracellular matrix componentssynthesized by constituents of the mammary fat pad.Further, mammary adipose tissue represents a significant store of lipid which, by itself and through itsderivatives, could influence the growth of mammaryepithelium in diverse ways. This review describes theintegral role of the mammary fat pad duringmammogenesis, emphasizing the point that species differencesmust be addressed if local growth and morphogenicmechanisms within the mammary gland are to beresolved.
Similar content being viewed by others
REFERENCES
G.R. Cunha and Y.K. Hom (1996). Role of mesenchymalepithelial interactions in mammary gland development. J. Mam. Gland Biol. Neoplasia 1:21–35.
M.C. Neville, D. Medina, J. Monks, and R.C. Hovey (1998). Editorial commentary: The mammary fat pad. J. Mam. Gland Biol. Neoplasia 3:109–116.
K. Kratochwil and P. Schwartz (1976). Tissue interaction in androgen response of embryonic mammary rudiment of mouse: Identification of target tissue for testosterone. Proc. Natl. Acad. Sci. U.S.A. 73:4041–4044.
T. Sakakura, Y. Sakagami, and Y. Nishizuka (1982). Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis. Dev. Biol. 91:202–207.
K. Kimata, T. Sakakura, Y. Inaguma, M. Kato, and Y. Nishizuka (1985). Participation of two different mesenchymes in the developing mouse mammary gland: Synthesis of basement membrane components by fat pad precursor cells. J. Embryol. Exp. Morph. 89:243–257.
G. Ailhaud, P. Grimaldi, and R. Négrel (1992). Cellular and molecular aspects of adipose tissue development. Ann. Rev. Nutr. 12:207–233.
L.G. Sheffield (1988). Organization and growth of mammary epithelia in the mammary gland fat pad. J. Dairy Sci. 71:2855–2874.
G.K. Bandyopadhyay, L-Y. Lee, R.C. Guzman, and S. Nandi (1995). Effect of reproductive states on lipid mobilization and linoleic acid metabolism in mammary glands. Lipids 30:155–162.
M.J. Paape and Y.N. Sinha (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.
R.C. Hovey (1997). The role of the mammary fat pad during mammogenesis. Ph.D. Thesis, Massey University, New Zealand.
R.C. Hovey, T.B. McFadden, and D.D.S. Mackenzie (1996). A procedure for the preparation of a parenchyma-free mammary fat pad in sheep. J. Dairy Sci. 79(Suppl. 1):146.
R. Anbazhagan, J. Bartek, P. Monaghan, and B.A. Gusterson (1991). Growth and development of the human infant breast. Am. J. Anat. 192:407–417.
R. Anbazhagan and B.A. Gusterson (1995). Ultrastructure and immunohistochem istry of the embryonic type of fat identified in the human breast. Anat. Rec. 241:129–135.
J. Russo and I.H. Russo (1987). Development of the human mammary gland. In M.C. Neville and C.W. Daniel (eds.), The Mammary Gland: Development, Regulation, and Function, Plenum Press, New York, pp. 67–93.
S. Bartow (1998). Use of the autopsy to study ontogeny and expression of the estrogen receptor gene in human breast. J. Mam. Gland Biol. Neoplasia 3:37–48.
K.B. DeOme, L.J. Faulkin, Jr., H.A. Bern, and P.B. Blair (1959). Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res. 19:515–520.
K. Hoshino (1978). Mammary transplantation and its histogenesis in mice. In A. Yokoyama, H. Mizuno, and H. Nagasawa (eds.), Physiology of Mammary Glands, Japan Scientific Societies Press, Tokyo, pp. 163–228.
M. Rebuffé-Scrive, J. Eldh, L.-O. Hafström, and P. Björntorp (1986). Metabolism of mammary, abdominal, and femoral adipocytes in women before and after menopause. Metabolism 35:792–797.
B.E. Elliott, S.-P Tam, D. Dexter, and Z.Q. Chen (1992). Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: Effect of estrogen and progesterone. Intl. J. Cancer 51:416–424.
K. Hoshino (1964). Regeneration and growth of quantitatively transplanted mammary glands of normal female mice. Anat. Rec. 150:221–236.
R.M. Akers (1990). Lactational physiology: A ruminant animal perspective. Protoplasma 159:96–111.
H.M. Jensen and S.R. Wellings (1976). Preneoplastic lesions of the human mammary gland transplanted into the nude athymic mouse. Cancer Res. 36:2605–2610.
L.G. Sheffield and C.W. Welsch (1988). Transplantation of human breast epithelia to mammary-gland-free fat-pads of athymic nude mice: Influence of mammotrophic hormones on growth of breast epithelia. Intl. J. Cancer 41:713–719.
J. Yang, T. Tsukamoto, N. Popnikolov, R.C. Guzman, X. Chen, J.H. Yang, and S. Nandi (1995). Adenoviral-med iated gene transfer into primary human and mouse mammary epithelial cells in vitro and in vivo. Cancer Lett. 98:9–17.
L.G. Sheffield and C.W. Welsch (1986). Transplantion of bovine mammary tissue to athymic nude mice: Growth subcutaneously and in mammary gland-free fat pads. J. Dairy Sci. 69:1141–1147.
S. Ellis and R.M. Akers (1995). Xenotransplantat ion of immortalized bovine mammary epithelial cells into the cleared fat pads of immunocompetent mice. J. Anim. Sci. 73(Suppl. 2):77–78.
T. Sakakura, Y. Nishizuka, and C.J. Dawe (1976). Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland. Science 194:1439–1441.
L. Rønnov-Jessen, O.W. Petersen, and M.J. Bissell (1996). Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiol. Rev. 76:69–125.
B.K. Vonderhaar (1988). Regulation of development of the normal mammary gland by hormones and growth factors. In M.E. Lippman, and R.B. Dickson (eds.), Breast Cancer: Cellular and Molecular Biology, Kluwer Academic Publishers, Boston/Dordrecht/London, pp. 251–266.
C.W. Daniel and G.B. Silberstein (1987). Postnatal development of the rodent mammary gland. In M.C. Neville, and C.W. Daniel (eds.), The Mammary Gland: Development, Regulation, and Function, Plenum Press, New York, pp. 3–36.
J.J. Berger and C.W. Daniel (1983). Stromal DNA synthesis is stimulated by young, but not serially aged mouse mammary epithelium. Mech. Aging Dev. 23:259–264.
G.B. Silberstein and C.W. Daniel (1982). Glycosaminogly cans in the basal lamina and extracellular matrix of the developing mouse mammary duct. Dev. Biol. 90:215–222.
H.A. Tucker (1987). Quantitative estimates of mammary growth during various physiological states: A review. J. Dairy Sci. 70:1958–1966.
R.D. Cardiff and S.R. Wellings (1999). The comparative pathology of human and mouse mammary glands. J. Mam. Gland Biol. Neoplasia 4 (in press).
S. Ellis, F.G. Edwards, and R.M. Akers (1995). Morphological and histological analysis of the prepuberal ovine mammary gland. J. Dairy Sci. 78(Suppl. 1):202.
T.L. Woodward, W.E. Beal, and R.M. Akers (1993). Cell interactions in initiation of mammary epithelial proliferation by oestradiol and progesterone in prepubertal heifers. J. Endocrinol. 136:149–157.
J.L. Fendrick, A.M. Raafat, and S.Z. Haslam (1998). Mammary gland growth and development from the postnatal period to postmenopause: Ovarian steroid receptor ontogeny and regulation in the mouse. J. Mam. Gland Biol. Neoplasia 3:7–22.
G. Shyamala and A. Ferenczy (1984). Mammary fat pad may be a potential site for initiation of estrogen action in normal mouse mammary glands. Endocrinology 115:1078–1081.
C.M. McGrath (1983). Augmentation of response of normal mammary epithelial cells to estradiol by mammary stroma. Cancer Res. 43:1355–1360.
G.R. Cunha, P. Young, Y.K. Hom, P.S. Cooke, J.A. Taylor, and D.B. Lubahn (1997). Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombination experiments. J. Mam. Gland Biol. Neoplasia 2:393–402.
E. Anderson, R.B. Clarke, and A. Howell (1998). Estrogen responsiveness and control of normal human breast proliferation. J. Mam. Gland Biol. Neoplasia 3:23–36.
C. Malet, A. Gompel, H. Yaneva, H. Cren, N. Fidji, I. Mowszowicz, F. Kuttenn, and P. Mauvis-Jarvis (1991). Estradiol and progesterone receptors in cultured normal human breast epithelial cells and fibroblasts: Immunocytochem ical studies. J. Clin. Endocrinol. Metabol. 73:8–17.
S. Ellis, T.B. McFadden, and R.M. Akers (1998). Prepuberal ovine mammary development is unaffected by ovariectomy. Dom. Anim. Endocrinol. 15:217–226.
A. Rotondi and F. Auricchio (1978). Oestrogen receptor of calf mammary gland. Biochem. J. 178:581–587.
R.C. Hovey, H.W. Davey, D.D.S. Mackenzie, and T.B. McFadden (1998). Multiple factors regulate the stromal expression of keratinocyte growth factor (KGF) in the ruminant mammary gland. (Submitted).
R.C. Hovey, T.B. McFadden, H.W. Davey, and D.D.S. Mackenzie (1996). Expression of growth factors during development of the ruminant mammary gland. J. Dairy Sci. 79(Suppl. 1):146.
T.L. Woodward, R.M. Akers, T.B. McFadden, H.T. Huynh, and J.D. Turner (1992) Estrogen mediated bovine mammary epithelial cell proliferation: Evidence of indirect action. J. Dairy Sci. 75(Suppl. 1):293.
D. R. Glimm, V.E. Baracos, and J.J. Kennelly (1990). Molecular evidence for the presence of growth hormone receptors in the bovine mammary gland. J. Endocrinol. 126:R5–R8.
H. Jammes, P. Gaye, L. Belair, and J. Djiane (1991). Identification and characterization of growth hormone receptor mRNA in the mammary gland. Mol. Cell. Endocrinol. 75:27–35.
H.C. Mertani, T. Garcia-Caballero, A. Lambert, F. Gerard, C. Palayer, J.M. Boutin, B.K. Vonderhaar, M.J. Waters, P.E. Lobie, and G. Morel (1998). Cellular expression of growth hormone and prolactin receptors in human breast disorders. Intl. J. Cancer 79:202–211.
D.L. Kleinberg (1998). Role of IGF-I in normal mammary development. Breast Cancer Res. Treat. 47:201–208.
L.G. Sheffield and R.R. Anderson (1986). Control of mammary gland fibroblast growth by insulin, growth hormone and prolactin. Cell Biol. Intl. Rep. 10:33–40.
T.B. McFadden, T.E. Daniel, and R.M. Akers (1990). Effects of plane of nutrition, growth hormone and unsaturated fat on growth hormone, insulin and prolactin receptors in prepubertal lambs. J. Anim. Sci. 68:3180–3189.
R.C. Hovey, H.W. Davey, D.D.S. Mackenzie, and T.B. McFadden (1998). Ontogeny and epithelial-stromal interactions regulate local IGF expression during ovine mammogenesis. Mol. Cell. Endocrinol. 136:139–144.
M. Edery, K. Pang L. Larson, T. Colosi, and S. Nandi (1985). Epidermal growth factor receptor levels in mouse mammary glands in various physiological states. Endocrinology 117:405–411.
S.Z. Haslam, L.J. Counterman, and K.A. Nummy (1992). EGF receptor regulation in normal mouse mammary gland. J. Cell. Physiol. 152:553–557.
S.Z. Haslam, L.J. Counterman, and K.A. Nummy (1993). Effects of epidermal growth factor, estrogen, and progestin on DNA synthesis in mammary cells in vivo are determined by the developmental state of the gland. J. Cell. Physiol. 155:72–78.
J. Sebastian, R.G. Richards, M.P. Walker, J.F. Wiesen, Z. Werb, R. Derynck, Y.K. Hom, G.R. Cunha, and R.P. DiAugustine (1998). Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis. Cell Growth Diff. 9:777–785.
S.Z. Haslam and G. Shyamala (1979). Effect of oestradiol on progesterone receptors in normal mammary glands and its relationship with lactation. Biochem. J. 182:127–131.
G. Shyamala, M.H. Barcellos-Hoff, D. Toft, and X. Yang (1997). In situ localization of progesterone receptors in normal mouse mammary glands: Absence of receptors in the connective and adipose stroma and a heterogeneous distribution in the epithelium. J. Steroid Biochem. Mol. Biol. 63:251–259.
P.J. Shughrue, W.E. Stumpf, and M. Sar (1988). The distribution of progesterone receptor in the 20–day-old fetal mouse: An autoradiographic study with [125I]progestin. Endocrinology 123:2382–2389.
S. Wang, L.J. Counterman, and S.Z. Haslam (1990). Progesterone action in normal mouse mammary gland. Endocrinology 127:2183–2189.
R.C. Hovey, T.B. McFadden, and D.D.S. Mackenzie (1994). Response of mammary epithelial cells to ovarian steroids is modulated by the mammary fat pad during the estrous cycle. J. Dairy Sci. 77(Suppl. 1):68.
A.A. Rasmussen and K.J. Cullen (1998). Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Res. Treat. 47:219–233.
A. Manni, B. Badger, L. Wei, A. Zaenglein, R. Grove, S. Khin, D. Heitjan, S. Shimasaki, and N. Ling (1994). Hormonal regulation of insulin-like growth factor-II and insulin-like growth factor binding protein expression by breast cancer cells in vivo: Evidence for stromal epithelial interactions. Cancer Res. 54:2934–2942.
R. Barraclough, D.G. Fernig, P.S. Rudland, and J.A. Smith (1990). Synthesis of basic fibroblast growth factor upon differentiation of rat mammary epithelial to myoepithelial-like cells in culture. J. Cell. Physiol. 144:333–344.
S. Chakravorti and L.G. Sheffield (1996). Acidic and basic fibroblast growth factor mRNA and protein in mouse mammary glands. Endocrine 4:175–182.
S. Coleman-Krnacik, and J.M. Rosen (1994). Differential temporal and spatial gene expression of fibroblast growth factor family members during mouse mammary gland development. Mol. Endocrinol. 8:218–229.
A. Plath, R. Einspanier, C. Gabler, F. Peters, F. Sinowatz, D. Gospodarowicz, and D. Schams (1998). Expression and localization of members of the fibroblast growth factor family in the bovine mammary gland. J. Dairy Sci. 81:2604–2613.
S. Chakravorti and L.G. Sheffield (1996). Hormonal regulation of acidic and basic fibroblast growth factor production and expression in mouse mammary gland. Endocrine 4:183–188.
P.S. Rudland, A.M. Platt-Higgins, M.C. Wilkinson, and D.G. Fernig (1993). Immunocytochem ical identification of basic fibroblast growth factor in the developing rat mammary gland: Variations in location are dependent on glandular structure and differentiation. J. Histochem. Cytochem. 41:887–898.
J.J. Gomm, J. Smith, G.K. Ryall, R. Baillie, L. Turnbull, and R.C. Coombes (1991). Localization of basic fibroblast growth factor and transforming growth factor-β1 in the human mammary gland. Cancer Res. 51:4685–4692.
R.D. Koos, P.K. Banks, S.E. Inkster, W. Yue, and A.M.H. Brodie (1993). Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcriptionpolymerase chain reaction. J. Steroid Biochem. Mol. Biol. 45:217–225.
S.E. Wilson, J. Weng, E.L. Chwang, L. Gollahan, A.M. Leitch, and J.W. Shay (1994). Hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and their receptors in human breast cells and tissues: Alternative receptors. Cell. Mol. Biol. Res. 40:337–350.
J.V. Soriano, M.S. Pepper, L. Orci, and R. Montesano (1998). Roles of hepatocyte growth factor/scatter factor and transforming growth factor-β1 in mammary gland ductal morphogenesis. J. Mam. Gland Biol. Neoplasia 3:133–150.
T.L. Woodward, R.M. Akers, T.B. McFadden, H.T. Huynh, and J.D. Turner (1992). Estrogen mediated bovine mammary epithelial cell proliferation: Evidence of indirect action. J. Dairy Sci. 75(Suppl. 1):293.
C. Birchmeier and W. Birchmeier (1998). Cellular interactions mediated by tyrosine kinase receptors during development: Driving forces for growth, motility and differentiation. In R.B. Dickson, and D.S. Salomon (eds.), Hormones and Growth Factors in Development and Neoplasia, Wiley-Liss Inc., New York, pp. 131–143.
L. Jin, A. Fuchs, S.J. Schnitt, Y. Yao, A. Joseph, K. Lamszus, M. Park, I.D. Goldberg, and E.M. Rosen (1997). Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer 79:749–760.
S.J. Weber-Hall, D.J. Phippard, C.C. Niemeyer, and T.C. Dale (1994). Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation 57:205–214.
Y. Hirai, A. Lochter, S. Galosy, S. Koshida, S. Niwa, and M.J. Bissell (1998). Epimorphin functions as a key morphoregulator for mammary epithelial cells. J. Cell Biol. 140:159–169.
K.S. Frazier and G.R. Grotendorst (1997). Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors. Intl. J. Biochem. Cell Biol. 29:153–161.
C.W. Daniel, S. Robinson, and G.B. Silberstein (1996). The role of TGF-β in patterning and growth of the mammary ductal tree. J. Mam. Gland Biol. Neoplasia 1:331–341.
M.H. Barcellos-Hoff (1996). Latency and activation in the control of TGF-β. J. Mam. Gland Biol. Neoplasia 1:353–363.
C.S. Nicoll (1997). Cleavage of prolactin by its target organs and the possible significance of this process. J. Mam. Gland Biol. Neoplasia 2:81–90.
L.A. Rudolph-Owen and L.M. Matrisian (1998). Matrix metalloproteinases in remodeling of the normal and neoplastic mammary gland. J. Mam. Gland Biol. Neoplasia 3:177–190.
S.H. Abou-El-Ala, K.W. Prasse, R. Carroll, A.E. Wade, S. Dharwadkar, and O.R. Bunce (1988). Eicosanoid synthesis in 7,12–dimethylbenz(a)anthracene-induced mammary carcinomas in Sprague-Dawley rats fed primrose oil, menhaden oil or corn oil diet. Lipids 23:948–954.
C.W. Welsch and D.H. O'Connor (1989). Influence of the type of dietary fat on developmental growth of the mammary gland in immature and mature female BALB/c mice. Cancer Res. 49:5999–6007.
T.B. McFadden, T.E. Daniel, and R.M. Akers (1990). Effects of plane of nutrition, growth hormone and unsaturated fat on mammary growth in prepubertal lambs. J. Anim. Sci. 68:3171–3179.
D.P. Rose (1997). Effects of dietary fatty acids on breast and prostate cancers: Evidence from in vitro experiments and animal studies. Am. J. Clin. Nutr. 66:1513S-1522S.
C.A. Carrington and H.L. Hosick (1985). Effects of dietary fat on the growth of normal, preneoplastic and neoplastic mammary epithelial cells in vivo and in vitro. J. Cell Sci. 75:269–278.
G.K. Bandyopadhyay, S.-I. Hwang, W. Imagawa, and S. Nandi (1993). Role of polyunsaturated fatty acids as signal transducers: Amplification of signals from growth factor receptors by fatty acids in mammary epithelial cells. Prostaglandins Leukotrienes and Essent. Fatty Acids 48:71–78.
R.C. Hovey, D.D.S. Mackenzie, and T.B. McFadden (1998). The proliferation of mouse mammary epithelial cells in response to specific mitogens is modulated by the mammary fat pad in vitro. In Vitro Cell. Dev. Biol. 34A:385–392.
K.L. Schmeichel, V.M. Weaver, and M.J. Bissell (1998). Structural cues from the tissue microenvironment are essential determinants of the human mammary epithelial cell phenotype. J. Mam. Gland Biol. Neoplasia 3:201–214.
T. Sakakura (1991). New aspects of stroma-parenchym a relations in mammary gland differentiation. Intl. Rev. Cytol. 125:165–202.
P.J. Keely, J.E. Wu, and S.A. Santoro (1995). The spatial and temporal expression of the α2β1 integrin and its ligands, collagen I, collagen IV, and laminin, suggest important roles in mouse mammary morphogenesis. Differentiation 59:1–13.
T.L. Woodward, J.W. Xie, and S.Z. Haslam (1998). The role of mammary stroma in modulating the proliferative response to ovarian hormones in the normal mammary gland. J. Mam. Gland Biol. Neoplasia 3:117–132.
I.H. Russo and J. Russo (1998) Role of hormones in mammary cancer initiation and progression. J. Mam. Gland. Biol. Neoplasia 3:49–61.
G. Chepko and G.H. Smith (1999). Mammary epithelial stem cells: Our current understanding. J. Mam. Gland Biol. Neoplasia 4:35–52.
Rights and permissions
About this article
Cite this article
Hovey, R.C., Mcfadden, T.B. & Akers, R.M. Regulation of Mammary Gland Growth and Morphogenesis by the Mammary Fat Pad: A Species Comparison. J Mammary Gland Biol Neoplasia 4, 53–68 (1999). https://doi.org/10.1023/A:1018704603426
Issue Date:
DOI: https://doi.org/10.1023/A:1018704603426