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Review
. 2010 Dec;2(12):a003178.
doi: 10.1101/cshperspect.a003178. Epub 2010 Aug 25.

Hormone action in the mammary gland

Cathrin Brisken  1 , Bert O'Malley
Affiliations
Review

Hormone action in the mammary gland

Cathrin Brisken et al. Cold Spring Harb Perspect Biol. 2010 Dec.

Abstract

A woman's breast cancer risk is affected by her reproductive history. The hormonal milieu also influences the course of the disease. The female reproductive hormones, estrogens, progesterone, and prolactin, have a major impact on breast cancer and control postnatal mammary gland development. Analysis of hormone receptor mutant mouse strains combined with tissue recombination techniques and proteomics revealed that sequential activation of hormone signaling in the mammary epithelium is required for progression of morphogenesis. Hormones impinge on a subset of luminal mammary epithelial cells (MECs) that express hormone receptors and act as sensor cells translating and amplifying systemic signals into local stimuli. Proliferation is induced by paracrine mechanisms mediated by distinct factors at different stages. Tissue and stage specificity of hormonal signaling is achieved at the molecular level by different chromatin contexts and differential recruitment of coactivators and corepressors.

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Figures

Figure 1.
Figure 1.
Scheme of female endocrine system. Different endocrine glands secreting mammotropic hormones are shown in ovals, hormones in boxes, highlighted in red are mammotropic hormones.
Figure 2.
Figure 2.
Control of mammary gland development by hormones. Different stages of mammary gland development are depicted. All hormone receptors are required in the mammary epithelium (pink boxes) with the exception of the GHR that is required in the stroma (yellow box) but also signals in the epithelium (dotted pink box). Red arrows indicate when different hormones are limiting with growth hormone and glucocorticoids being required throughout mammary gland development. Dotted arrows illustrate hormonal regulation of HR expression.
Figure 3.
Figure 3.
Local control of mammary gland development by estrogens. For explanations see text. As cell proliferation in response to estrogens increases at ductal tips the basal lamina becomes discontinuous until it eventually disappears right around the cap cells of the growing TEBs.
Figure 4.
Figure 4.
Factors involved in mammary gland development. Work of many laboratories led to the identification of many genes important in mammary gland development that are summarized in the scheme.
Figure 5.
Figure 5.
General structure of nuclear hormone receptors. Steroid receptors differ in details, but are generally composed of multiple (5–6) structural domains (A–F), and functional domains (in colors). The functions of these receptor regions are listed in the figure: AF1 (activation function one); DBD (DNA binding domain); H (hinge domain); AF2 (activation function two). The AF1 and AF2 provide the main surfaces that interact with other transcription factors to transduce the signal of the hormonal ligand, which binds to the ligand binding domain (LBD, orange color).
Figure 6.
Figure 6.
Nuclear Receptor (NR) dependent transcription, RNA splicing, and termination. NR regulated transcription begins by translocation of a hormone activated nuclear receptor dimer to hormone binding sequences in DNA near target genes. The receptor then must recruit, in sequence, a series of protein complexes that carry out all of the subreactions of DNA transcription: BRG/Brm complex regulates chromatin (nucleosome) remodeling; SRC/CARM/pCAF/CBP covalently modifies nucleosomes through mainly acetylation; TRAPs/pTEFb allows elongation of RNA polymerase on the gene; CAPER/CoAA/ASC-2/SRC/ALR provides splicing regulation; and E3 ligases bound to SRCs lead to degradations of the activated receptor and also the coregulators at the site of gene expression (after a short period of function). The General Transcription Factors (GTFs; TBP/TAFs) allow RNA polymerase to functionally transcribe the gene. Capping, elongation, termination are general aspects of RNA synthesis that result in the production of pre-mRNAs.
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