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Information networks in the mammary gland

Nature Reviews Molecular Cell Biology volume 6, pages 715–725 (2005)Cite this article

Key Points

  • Mammary gland development occurs in distinct stages starting in the embryo. However, the main part of this process proceeds in the adult female during pregnancy, which culminates in lactation when the organ reaches its ultimate goal — milk synthesis and secretion to nourish the offspring.

  • After each lactation, the gland regresses and the bulk of alveolar cells die, only to be rebuilt during the following pregnancy from pluripotent precursors.

  • The functional milk-producing unit in the mammary gland, the alveolus, is composed of luminal (secretory) and basal (myoepithelial) cells, which are descendants of a common progenitor cell.

  • Proliferation and differentiation of mammary alveolar epithelium during pregnancy is under the strict control of female lactogenic hormones, which exert their action by direct and indirect mechanisms.

  • Prolactin and placental lactogens signal through the prolactin receptor and are the primary inducers of mammary development during pregnancy. Their signal is executed by the transcription factor STAT5 (signal transducer and activator of transcription-5), which itself is central in the processing of hormone signals emanating from several receptors, including ERBB4, at different steps during development.

  • A number of genes have been identified that are controlled by STAT5, and the proteins they encode direct many facets of alveologenesis. These genes encode other transcription factors such as ELF5; growth factors such as receptor activator of nuclear factor κB (NF-κB)-ligand (RANK-L), which functions in a paracrine fashion to activate the NF-κB pathway; cell-cycle regulators such as cyclin D1; structural proteins that are components of gap junctions, which regulate cell communication; and milk protein genes.

  • Mouse models with specific gene deletions that disrupt distinct features of mammary gland development have been instrumental in understanding the complexity of endocrine and paracrine signals that control the formation of this organ. Using these mice, it has been possible to identify key molecules and develop an integrated network of signals that coordinate cell growth, survival and death, cell renewal and differentiation in the mammary gland.

Abstract

Unique developmental features during puberty, pregnancy, lactation and post-lactation make the mammary gland a prime object to explore genetic circuits that control the specification, proliferation, differentiation, survival and death of cells. Steroids and simple peptide hormones initiate and carry out complex developmental programmes, and reverse genetics has been used to define the underlying mechanistic connections.

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Figure 1: Mouse mammary gland development during puberty, pregnancy and lactation.
Figure 2: Cell lineages in mammary epithelium.
Figure 3: Progression of differentiation during pregnancy.
Figure 4: Processing of cytokine information during pregnancy.

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Acknowledgements

L.H. and G.W.R. are supported by the Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases).

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Authors and Affiliations

  1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Lothar Hennighausen & Gertraud W. Robinson

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Correspondence to Lothar Hennighausen.

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DATABASES

Swiss-Prot

Bcl-X

CAV1

Cx26

Cx32

ELF5

ERBB1

ERBB2

ERBB3

ERBB4

gp130

JAK2

PRL

PRLR

RANK

RANK-L

SOCS1

SOCS3

STAT3

STAT5A

STAT5B

FURTHER INFORMATION

Lothar Hennighausen's laboratory

Glossary

MAMMARY GLAND

A secretory organ in mammals that produces milk during lactation to feed the young. The gland is composed of alveoli, ducts and a stromal compartment.

LIPID RAFTS

Lateral aggregates of cholesterol and sphingomyelin that are thought to occur in the plasma membrane.

GAP JUNCTION

Communicating junction (permeant to molecules up to 1 kDa) between adjacent cells, which is composed of 12 connexin protein subunits, six of which form a connexon or hemichannel contributed by each of the coupled cells.

ANLAGE

The embryonic primordium of an organ.

MAMMARY DUCT

An epithelial structure transporting milk.

SIDE BRANCHES

Small ducts that branch off a major duct during ductal elongation.

PLACENTAL LACTOGENS

Peptide hormones produced by the placenta during pregnancy. These hormones bind to the prolactin receptor and are involved in the induction of proliferation and functional differentiation of luminal cells.

MAMMARY STROMA

Connective tissue supporting the epithelial compartment of the mammary gland. The prevalent cell types are fat cells (adipocytes) in addition to fibroblasts, vasculature and haematopoietic cells.

ALVEOLI

Ball-shaped structures composed of two cell types surrounding a central lumen. The luminal cells synthesize and secrete milk components and the basal cells are contractile.

LUMINAL, SECRETORY CELLS

Cells lining the lumen of alveoli. They synthesize milk proteins and secrete milk.

BASAL, MYOEPITHELIAL CELLS

Cells that surround the luminal cells as a layer. They contain smooth muscle actin and contract in response to oxytocin to mediate milk let-down through the main ducts to the nipple.

ADIPOCYTE

A fat cell.

STEM CELLS

Cells that have the capacity for self renewal and generation of differentiating daughter cells.

PARACRINE

Describing, or relating to, a regulatory cell that secretes an agonist into intercellular spaces from which it diffuses to a target cell other than the one that produces it.

OSTEOCLAST

A mesenchymal cell that can differentiate into a bone-degrading cell.

LACTOTROPHS

Prolactin-producing cells in the anterior lobe of the pituitary gland.

CYTOKINES

Initially identified as regulatory polypeptides secreted by immune cells, this family also contains non-immune molecules such as growth hormone and prolactin.

CORPUS LUTEUM

A temporary endocrine gland in the ovaries that produces progesterone.

HAPLO-INSUFFICIENCY

A state in which loss of only one of two alleles of a gene detectably disables its function.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so competes with normal proteins, thereby impairing protein function.

CRE-LOXP-MEDIATED RECOMBINATION

A tool for cell-specific gene deletion. It uses Cre recombinase from bacteriophage P1, which mediates intra- and intermolecular site-specific recombination between loxP sites.

MAMMARY ALVEOLUS

The functional unit in the mammary gland that produces milk.

CAVEOLAE

Specialized domains in the plasma membrane that form small invaginations and are involved in vesicular trafficking and cell signalling.

ALVEOLAR BUD

A small evagination from a main duct that forms during the oestrous cycle and at the initiation of pregnancy.

ACTIVATION LOOP

A conserved structural motif in kinase domains that needs to be phosphorylated for full activation of the kinase.

BCL2

An anti-apoptotic protein. It is the founding member of the BCL2 family of pro- and anti-apoptotic proteins.

ETS FAMILY

Proto-oncogene family related to v-ets, one of the oncogenes of the acutely transforming avian erythroblastosis virus E26.

EXOCRINE GLAND

A gland of epithelial origin that secretes (directly or through a duct) onto an epithelial surface.

FORWARD GENETICS

A genetic analysis that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.

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Hennighausen, L., Robinson, G. Information networks in the mammary gland. Nat Rev Mol Cell Biol 6, 715–725 (2005). https://doi.org/10.1038/nrm1714

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