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Hormone Action in the

Cathrin Brisken1 and Bert O’Malley2

1Ecole Polytechnique Fe´de´rale de Lausanne (EPFL), ISREC - Swiss institute for experimental cancer research, NCCR Molecular Oncology, SV2.832 Station 19, CH-1015 Lausanne, Switzerland 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 Correspondence: cathrin.brisken@epfl.ch

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, , and prolactin, have a major impact on breast cancer and control postnatal mammary gland development. Analysis of hormone mutant mouse strains com- bined with tissue recombination techniques and proteomics revealed that sequential acti- vation 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.

reast cancer is the most frequent cancer in mouse mammary gland has been instrumental Bwomen and the second leading cause of can- in providing new insights into the mechanisms cer deaths among women. To better understand by which hormones act in the mammary gland. the genetic alterations responsible for breast A numberof features make the mouse mam- cancer, it is critical to first understand the mech- mary gland a particularly attractive experimen- anisms regulating normal mammary gland tal system. Being the only organ that undergoes development. Increased interest in the field has most of its development postnatally, it is partic- led to the identification of a large number of ularly suited for studying developmental pro- important for mammary gland develop- cesses; it is readily amenable to experimental ment (reviewed in Tanos and Brisken 2008). manipulation and can be easily accessed as it A woman’s risk for breast cancer is linked localizes to the underside of the ventral skin. to her reproductive history and with her life- Furthermore, mammary gland tissue is abun- time hormonal exposure; hormones also influ- dant; there are 5 pairs of mammary glands in ence the course of the disease. The same hor- mice, and cells can be isolated in large numbers. mones that affect breast carcinogenesis control The versatile tools of mouse genetics can be postnatal mammary gland development. The combined with powerful tissue recombination

Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey Rosen Additional Perspectives on The Mammary Gland as an Experimental Model available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a003178 Cite this article as Cold Spring Harb Perspect Biol 2010;2:a003178

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C. Brisken and B. O’Malley

techniques to generate chimeric glands, as we adulthood trigger side branching; pregnancy will illustrate in this article. enhances side branching and induces alveolo- genesis with lactational differentiation followed DEVELOPMENT OF THE MOUSE by involution at weaning (Brisken 2002). In the MAMMARY GLAND late fifties, a series of experiments defined the minimal hormonal requirements for mammary Twomajor phases can be distinguished in mam- gland development in mice (Nandi 1958) and mary gland development: hormone-indepen- rats (Lyons 1958). Endocrine ablation was dent up to puberty, and hormone-dependent achieved by surgically removing the major thereafter. sources of reproductive hormones from mature Hormone-Independent Mammary Gland females, the ovaries, which secrete estrogens Development and progesterone, the pituitary gland, a major source of growth hormone (GH) and prolactin The mammary gland develops from a thicken- (Prl), and for some experiments the adrenal ing in the ventral skin during embryogenesis glands, which release cortisol and precursors (see Wysolmerski in this issue) that grows into of sex steroids (see Fig. 1). Hormone replace- a rudimentary ductal tree by birth. Until pub- ment in hormone-deprived animals established erty, the mammary gland grows isometrically that additive and sequential treatment with to the rest of the body. Although hormone 17-b-estradiol, progesterone, and prolactin in receptors are expressed before puberty (Stumpf conjunction with cortisol and GH can recapitu- et al. 1980; Hovey et al. 2001; Grimm et al. 2002) late mammary gland development. and the fetus is exposed to high levels of mater- nal and placental hormones, it is generally held that the female mammary gland develops up to MECHANISMS OF IN VIVO HORMONE puberty in a hormone-independent fashion ACTION because no overt mammary gland phenotype is observed before puberty in a variety of hor- Systemic versus Local Effects mone receptor deficient animals (see the follow- Hormones act on multiple organs and affect ing discussion). Elegant work with androgen each other’s synthesis and secretion. Estrogens, receptor mutant mice revealed that males of cer- for instance, control the reproductive tract and tain strains do not have nipples, because during the gonads as well as the skeletal system and embryogenesis, secreted by the the cardiovascular system (Stampfer et al. maturing testes induces apoptosis of the epithe- 1991; McDonnell and Norris 1997; Couse and lial bud by activation of sig- Korach 1999). They also act on the pituitary naling in the mammary stroma (Durnberger gland to stimulate prolactin synthesis and secre- and Kratochwil 1980). Perinatal exposure to tion (Fig. 1) (Scully et al. 1997). Prolactin con- exogenous hormones or endocrine disruptors, trols the luteal body and hence progesterone i.e., substances that can activate and/or inhibit synthesis in mice (Bachelot and Binart 2007), hormonal signaling, can result in subsequent and induces transcription of ERa in different aberrant development (Bern et al. 1983, 1987), tissues (Frasor and Gibori 2003). Because of suggesting that even when hormone receptors such interactions it is impossible to discern in are not physiologically required, their untimely physiological settings to what extent the effects activation can perturb development. of a given hormonal stimulus on the mammary gland are a result of direct hormone action on Hormone-Dependent Mammary Gland this tissue or secondary to stimulation of other Development organs. Through targeting in the mouse Hormone-dependent mammary gland devel- germ line, mice were generated that are unre- opment occurs after puberty and results in sponsive to individual reproductive hormones, ductal elongation; recurrent estrous cycles in because they lack the cognate receptors. All

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Hormone Action

Different input

Hypothalamus

GnRH

Prolactin Ant.pituitary

Growth hormone

Adrenal glands

FSH/LH

Estrogens Inhibin Ovaries Activin Progesterone

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.

the receptor-deficient mouse strains are viable a wt host, inguinal mammary fat pads of 3-week- but have reproductive abnormalities; ERa, old wt females were cleared of endogenous ERb, PR, and PrlR deficient are sterile for differ- epithelium and engrafted on one side with ent reasons (Lydon et al. 1995; Ormandy et al. ERa-/- epithelium and contralaterally with wt 1997; Dupont et al. 2000; Antal et al. 2008), epithelium (Mallepell et al. 2006). When wt epi- whereas GHR-/- mice have delayed sexual thelium is grafted into such “cleared fat pads,” it maturation (Zhou et al. 1997). grows to fill the entire fat pad and behaves like endogenous epithelium (DeOme et al. 1959). Within a few weeks, the graft grows to fill the Estrogens fat pad through dichotomous branching; cell In ERa-/- females, mammary gland develop- proliferation concentrates at the tip of the ducts ment is indistinguishable from that of wild-type that enlarge to spoonlike shapes called terminal (wt) littermates until the age of puberty, there- end buds (TEBs) (Daniel and Silberstein 1987). after no development occurs as assessed by In contrast, ERa-/- mammary epithelium gra- whole mount stereomicroscopy and histology. fted contralaterally and hence exposed to the For the former, mammary glands are cleared of same hormonal milieu, failsto growat all. During fat, stained, and visualized at 5- to 120-fold mag- pregnancy, the wt grafts display side branching nification. The entire gland, about 123cm3 in and alveoli bud off all over the ductal treewhereas size can be examined up to a resolution that the ERa mutant epithelium remains a rudiment corresponds to several cell diameters. Histologi- (Mallepell et al. 2006). This indicates that epithe- cal analyses complement morphology at cellular lial ERa signaling is required for ductal elonga- resolution. tion and, directly or indirectly, for subsequent The ERa is expressed both in the mammary side branching and alveologenesis. epithelium and the mammary stroma (Daniel To assess the role of stromal ERa signaling, et al. 1987). Toassess the role of epithelial intrin- ERa-/- fat pads were grafted onto the abdomi- sic ERa signaling in the context of wt stroma in nal muscle wall of wt hosts, and a piece of wt

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C. Brisken and B. O’Malley

epithelium was inserted into them, thereby gen- mammary gland development (Mulac-Jericevic erating mice that specifically lack ERa in the fat et al. 2000, 2003). pad of one of their mammary glands. In these chimeric glands, grafted wt epithelium grows Prolactin and Others out normally and shows alveolar differentiation whereas endogenous mutant epithelium coex- Grafting experiments with PrlR-/- epithelium isting in the same fat pad remains rudimentary showed that ductal outgrowth and side branch- (Mallepell et al. 2006). Thus, the presence of the ing can occur in the absence of epithelial PrlR sig- stromal ERa is not required for mammary naling (Brisken et al. 1999). However, the Prl gland development. signaling pathway is required for alveologenesis ERb-/- females show some delay in side and differentiation of MECs into milk producing branching, which may be attributable to irregu- cells during late pregnancy. Morphological hall- lar estrous cycles related to perturbed ovarian marks of secretory differentiation such as fat function in these mutants that results in droplets and “granular” cytoplasm are absent. decreased progesterone secretion (Antal et al. Expression of specific differentiation markers 2008). Hence the physiological role of ERb in such as the milk b-casein and whey the mammary epithelium and the mammary acidic proteins (WAP) mRNA is lost in PrlR-/- stroma, where it has been reported to be more epithelium and STAT5a phosphorylation is highly and widely expressed than the ERa undetectable (Brisken et al. 1999; Gallego et al. (Cheng et al. 2004), remains unclear. GPR30, 2001). Wt epithelium grafted into PrlR-/- stroma a G- coupled receptor, has been impli- developed normally (Ormandy et al. 2003). cated in mediating rapid nongenomic estrogen GHR-/- mammary epithelium develops signaling in different cellular systems, including and differentiates normally when grafted to breast cancer cell lines (reviewed in Prossnitz cleared fat pads indicating that epithelial GHR et al. 2007); when deleted from the mouse signaling is not limiting for mammary gland germ line, no abnormalities in the reproductive development (Gallego et al. 2001). It was sug- system were found (Otto et al. 2009). gested that GH acts on the mammary stroma because injections of GH resulted in STAT5a phosphorylation and STAT5a/b heterodimer Progesterone formation to a comparable extent in intact Like ERa, PR is expressed in both epithelial and mammary glands and cleared fat pads; however, stromal compartments in the mouse mammary it cannot be excluded that effects of the hor- gland (Haslam and Shyamala 1981; Haslam mone on other organs may be involved as 1989). PR-/- epithelial grafts grow out normally well. GH induces the production of IGFs in when grafted to cleared fat pads of wt hosts but the liver, and IGF signaling is important for fail to side branch and do not form alveoli, in- mammary gland development. Similarly, GH dicating that epithelial intrinsic progesterone injection was shown to elicit Stat5 phosphoryla- receptor signaling is required for side branching tion in myoepithelial cells as detected by im- and alveologenesis. Deletion of PR in the stroma munohistochemistry (LeBaron et al. 2007). For did not affect mammary gland development as a more extensive review of GH and Prl lacto- assessed by whole mount microscopy (Lydon genic functions see (Trott et al. 2008). et al. 1995; Brisken et al. 1998). PRs are com- Taken together, a picture emerges in which posed of two proteins that are expressed from a estrogens, progesterone, and prolactin act single gene as a result of transcription from two sequentially on the mammary epithelium in alternative promoters (Kastner et al. 1990) both synergy with corticosteroids to orchestrate of which are expressed in the mouse mammary mammary gland development in the presence gland (Aupperlee et al. 2005). Characterization of GH acting possibly via stromal and epithelial of the mutant strains lacking one or the other GHRs (Fig. 2). During puberty, estrogen levels form revealed that PR-B is uniquely required for increase first to set the stage for progesterone,

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Hormone Action

Growth hormone

Glucocorticoids GHR GHR GR

Estrogen Progesterone Prolactin

ERα PR PrlR

Alveologenesis/lactogenic differentiation Ductal elongation/bifurcation Side branching

Rudimentary ductal system Puberty Estrous cycles Pregnancy

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.

by inducing the expression of the PR (Haslam at different levels during the preceding stages and Shyamala 1979). This so-called “estrogen of ductal outgrowth and side branching. priming” occurs in most progesterone target Prolactin and progesterone may enhance duc- tissues. Cyclic secretion of progesterone is estab- tal outgrowth by inducing ERa expression. lished as the mouse attains sexual maturity and Furthermore, targeted gene deletion in the this coincides with the ducts reaching the edges germ line may mask physiologic functions of of the fat pad by dichotomous branching. Once a given gene product as mutant tissues may side branches are established by midpregnancy, have time during development to compensate further alveologenesis requires epithelial pro- for the loss of a particular gene product. Plas- lactin signaling (Brisken 2002). This sequential ticity may result in compensation, and it is action ensures that the distinct morphological conceivable that if a hormone receptor was steps occur in an orderly manner; in this way, efficiently abrogated at a later stage, different all of the ducts are established before alveoli and/or more severe phenotypes would be bud and they find adequate space to unfold discerned. and to be drained efficiently. The endocrine glands determine the hor- This sequential alignment defined by the monal milieu and are strictly controlled by the stages at which particular hormone receptors hypothalamo-pituitary axis, which in turn are limiting should not detract from the fact reacts to feed back from the periphery (see that at any given time all hormones are present Fig. 1). In addition to the main players, which albeit at different concentrations in the blood are limiting, a number of additional systemic and/ or locally and that they interact with factors are likely to be involved in fine-tuning each other at multiple levels. As examples, pro- the system such as vitamin D (Zinser et al. lactin is only limiting for alveologenesis, yet, it 2002; Zinser and Welsh 2004) and thyroid hor- may synergize with estrogens and progesterone mones. In recent years it has become apparent

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C. Brisken and B. O’Malley

that adipose tissue, in particular visceral, is a role in milk ejection during lactation. About actively secreting adipokines and cytokines a third of the luminal epithelial cells express such as leptin, adiponectin, and TNFa, which ERa and PR (Fig. 3), and expression largely have important implications for metabolic syn- overlaps, at least in human breast epithelial cells dromes (Antuna-Puente et al. 2008). Evidence (Clarke et al. 1997). has accumulated that some of these factors Across species, most proliferation occurs in may affect breast carcinogenesis by altering the steroid receptor negative cells in the adult mam- tumor microenvironment; in the mouse, adipo- mary epithelium with only a few ERa positive nectin haploinsufficiency promotes MMTV- cells incorporating labeled nucleotides (Clarke PyVT induced mammary tumors in different et al. 1997; Russo et al. 1999; Seagroves et al. genetic backgrounds (Lam et al. 2009). The 2000; Grimm et al. 2002). Because the ERa pro- physiologic role of the mammary fat pad as an tein is rapidly degraded by the proteasome upon endocrine gland, the role of the factors it transactivation (Reid et al. 2003), it was pro- secretes, and the mechanisms through which posed that ERa expression is down modulated they affect mammary gland development have in cells that have entered the cell cycle as a con- not been explored. Intriguingly, mice lacking sequence of estrogen stimulation (Cheng et al. leptin (Lepob/Lepob) or the leptin receptor 2004). When ERa-/- MECs were mixed with (Leprdb/Leprdb) have a rudimentary, atrophic wt MECs in vitro and this mixture was subse- ductal tree at 1 or 2 yr of age (Hu et al. 2002). quently used to reconstitute cleared fat pads, it The mammary epithelium itself secretes PTHrP, was demonstrated that in the presence of sur- important for nipple development (Kobayashi rounding wt MECs, ERa-/- MECs proliferate et al. 2005) and prolactin that enhances mam- extensively and contribute to all cellular com- mary epithelial cell proliferation during lacta- partments in the mammary gland, that is, tion (Naylor et al. 2003). Finally, data from body and cap cells of TEBs and myoepithelial humans indicate that local concentrations of and luminal cells of the mature ducts. These 17-b-estradiol and its metabolites reflect not data indicate that estrogens can elicit prolifera- only serum estrogen levels but also local pro- tion by a paracrine mechanism and that ERa-/- duction resulting from conversion of C19 ste- cells can actively proliferate in response to estro- roids such as androstendione and testosterone gens (Mallepell et al. 2006). The same is the case into estrogens by aromatase expressed within for progesterone, as PR-/- MECs form side the gland (Santen et al. 2009 and references branches and alveoli in the context of chimeric therein) highlighting that many other factors epithelia with wt MECs (Brisken et al. 1998). impinge on hormone signaling. Depending on the developmental stage and the predominant hormonal stimulus, the sce- narios at the cellular level are different. Intercellular Signaling (Paracrine During puberty, estrogens are the major Mechanisms) mitogenic stimulus and signal via ERa.Insexu- How does activation of hormone receptors by ally mature females, estrogens elicit little prolif- their respective ligands elicit proliferation and eration but are permissive for the strongly morphogenesis? A closer look at the mammary mitogenic effects of progesterone. Experiments epithelium reveals that it consists of two cell with amphiregulin-/- mammary epithelia compartments, luminal and basal. Luminal grafted into cleared wt fat pads, revealed that cells are connected by tight junctions and amphiregulin is an essential mediator of form a single layer of polarized epithelium estrogen-induced proliferation during puberty. around the ductal lumen. The basal compart- Amphiregulin is the only EGF family member ment comprises all the cells that do not touch whose transcription is strongly induced by the lumen; these include progenitors and myo- 17-b-estradiol in the peripubertal mammary epithelial cells, which are contractile, form a gland (Ciarloni et al. 2007). Amphiregulin meshwork around the luminal cells, and play is a membrane-anchored protein that can be

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Hormone Action

“Sensor cell” Estrogens ER/PR positive Luminal epithelium ?

TACE FGFR2

Myoepithelium Amphiregulin

Basal lamina Fibroblasts EGFR

FGF7, FGF10 ?

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.

cleaved and released by ADAM17/TACE (Sun- basal lamina is disrupted and the outer epithelial narborg et al. 2002). Consistent with amphire- cells, the highly proliferative cap cells are in direct gulin being released and thereby activated by contact with stromal cells. TACE, in vivo ablation of ADAM17 from the The question arises as to the identity of the epithelium blocks ductal outgrowth mimicking mitogenic signal that makes MECs proliferate. both amphiregulin and ERa-/- phenotypes Very attractive candidates are FGF7 and 10. (Sternlicht et al. 2005). Amphiregulin binds to Messenger RNA expression of both factors is and activates the epidermal re- induced in the mammary fat pad following ceptor (EGFR), which is expressed in the stro- estrogen stimulation, and it is conceivable that mal compartment during ductal elongation induction of their mRNAs is mediated by the (Schroeder and Lee 1998). Recombination EGFR in the stroma in response to amphiregu- experiments with EGFR-/- tissue showed that lin. Their cognate receptor, FGFR2, is required stromal EGFR expression is required for ductal in the epithelial compartment for ductal elon- outgrowth whereas epithelial deletion does not gation (Lu et al. 2008). When FGFR2 was interfere with ductal development (Wiesen deleted at later stages through recurrent activa- et al. 1999). Initially, this epithelial-stromal tion of the MMTV-cre in response to proges- crosstalk may not be efficient as the amphiregu- terone stimulation during side branching, the lin secreted by ERa positive luminal cells needs mutant MECs persisted, indicating that FGFR2 to be transported through the myoepithelial is specifically required for estrogen-induced layer and the basal lamina before it can dock proliferation. to its cognate receptor on a stromal fibroblast. In case of progesterone and prolactin, the However, as hormonal stimulation persists, pro- local signaling circuitry is less well understood. liferation increases substantially at the tips of the Wnt-4 is required in the mammary epithelium ducts and they enlarge to form spoon-shaped for side branching (Brisken et al. 2002) and structures called terminal end buds (TEBs). The the TNF family member RANKL was identified bulk of cells within these structures are called as a progesterone target gene. Based on the ob- body cells. The outercell layerof the TEBsis con- servation that RANKL protein localizes to PR tinuous with the myoepithelium of the subtend- positive cells, which occur next to BrdU incor- ing mature duct and consists of cap cells, which porating cells, it was proposed that RANKL is lack intercellular adhesion. Around the TEB the a paracrine mediator of progesterone-induced

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C. Brisken and B. O’Malley

proliferation (Mulac-Jericevic et al. 2003). Con- Molecular Mechanisms of Differential sistent with this scenario, functional data show Hormone Action that ectopic expression of RANKL using a How can the steroid hormones elicit completely MMTV transgene results in side branching in different effects in different tissues and develop- the absence of pregnancy (Fernandez-Valdivia mental contexts? Identification of new players et al. 2009). in (NR) signaling has shed IGF-2 has been implicated as an important new light on the molecular underpinnings in mediator of PrlR signaling upstream of cyclin recent years. D1 mediating prolactin effects (Brisken et al. 2002; Hovey et al. 2003). TGFb signaling has been implicated as a growth inhibitory signal in Structural Features of Estrogen and Progesterone Receptors mammary gland development acting through Wnt5a and important in both estrogen and pro- The chemical signals of estrogen and progester- gesterone induced morphogenesis (Roarty and one are transduced by their specific intracellular Serra 2007 and references therein). An overview steroid receptors (SRs). SRs are functionally of the factors that have been implicated in mam- composed of three main domains: a hormone- mary gland development is shown in Figure 4. independent activation function 1 (AF1 do- The paracrine mode of action ensures that main),a DNA-bindingfunction(DBDdomain), the behavior of different cells is coordinated; and hormone-dependent activation function this is important as epithelial cell proliferation 2 (AF2 domain) (Fig. 5) (Mangelsdorf et al. in a glandular organ such as the breast results 1995). The a (ERa) gene, in morphogenesis with new ducts and alveoli which produces a protein of 595 amino acid being formed. Furthermore, in this way the hor- residues with a molecular mass of 66 kDa, monal signals in nano or picomolar ranges are is composed of six structural subdomains amplified, a scenario that is reiterated clearly corresponding to the three functional regions at the molecular level by the use of transcrip- described above (Evans 1988; Bourguet et al. tional coactivators as discussed later. 2000; Klinge 2000; Nagy and Schwabe 2004).

Estrogen Progesterone Prolactin STAT5a/b SRC3/AIB1 cEBPb Cited-1 IL-4/13/STAT6 P190-BRhoGAP a6 Wnt 5a PTEN ErbB4 Wnt 5b EGF MMP3 IGF-1 Wnt 6 IGF-2 TGFb3 b Netrin neogenin 1 Integrin b p27 TGF 2 TGFa a- Slit robo MMP2 Laminin Wnt 4 RANKL TACE Heregulin Amphiregulin PEA3 Cyclin D1 ID4 ID2 , , elf-5 Patched PrlR FGF-4 GATA -3 ERa PR

EGF HGF CSF-1 FGF 10 Activin Wnt 10b FGF 7 ihh IGF-1 Wnt 2

Figure 4. Factors involved in mammary gland development. Workof many laboratories led to the identification of many genes important in mammary gland development that are summarized in the scheme.

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Hormone Action

Domains: A / B C D E (F)

N AF1 DBD H AF2 C

Functions: AF1 – Activation function 1 – hormone independent activation DBD – DNA binding domain – binds to specific hormone response elements H – Hinge region – protein-protein interactions; post-translational modifications AF2 – Activation function 2 – ligand binding domain; ligand dependent functions; protein-protein interactions

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).

The A and B structural subdomains of ERa interact with liganded ERa (Klinge 2000; functionally belong to the AF1 region of the Lonard and O’Malley 2007, 2008a, 2008b). receptor. This region is implicated in the Finally, there is the carboxy-terminal F subdo- hormone-independent transcriptional activa- main whose role in the receptor is less clear, tion of the receptor. The C subdomain repre- but has been shown to be involved in part in sents the DNA binding domain (DBD) of the receptor dimerization (McKenna et al. 1999). molecule. It is composed of two zinc-finger With minor variations, the functional do- motifs responsible for receptor interaction mains contained in the ERa and ERb molecules with the DNA. The D subdomain of ERa,or also can be found in the PR, and all other steroid the hinge region is a 39-amino-acid long linker hormone receptors. The PR gene is unique in between the DNA and ligand binding regions that it codes for two receptor isoforms (PR-A (LBD) of ERa. Functionally, it contains a and PR-B), which display overlapping but also nuclear localization signal (NLS) and it is impli- distinct gene regulatory properties in relaying cated in interaction with some coregulator mol- the progesterone signal. Distinct tissue-specific ecules. The E structural subdomains of the ERa reproductive responses to progesterone exhib- molecule encompass the ligand-binding surface ited by these twoprogesterone receptor isoforms and the AF2 functional domain. The AF2 are caused by regulation of distinct subsets of domain is responsible for the ligand dependent progesterone-dependent target genes by the transcriptional activity of ERa. The ligand- individual PR isoforms. (Conneely et al. 2003). binding region is composed of 5 a helixes (helixes 3, 6, 8, 11, and 12), which form a hydro- Mechanisms of Regulation of Steroid phobic ligand-binding cleft (Evans 1988; Bour- Receptor Actions by Coregulators guet et al. 2000; Klinge 2000; Nagy and Schwabe 2004; Pike 2006). Upon binding to E2, this In steroid receptor containing cells, a new class region undergoes a conformational change of molecules, termed coregulators, was discov- such that helix 12 is displaced so as to cover ered over a decade ago (On˜ate et al. 1995). the ligand-binding pocket. This change in the The coregulators are generally enzymes capable position of helix 12 creates a new interacting of modifying chromatin proteins, the basal plane at the surface of the molecule, which is transcriptional machinery, and other coregula- then used for the recruitment of coactivator tors. The coregulators are composed of coacti- molecules. Coactivator proteins contain one or vators, which provide positive enhancement to more LXXLL helical amino acid motifs that gene expression, and corepressors, which are

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C. Brisken and B. O’Malley

employed to suppress gene expression. These ubiquitination, SUMOylation and acetylation. regulatory molecules provide the ability to fine- In the case of coregulators, it has been observed tune our genes and activate them in functional that a combination of such modifications can combinations. Recently, we have come to realize lead to multiple functionally distinct activities that coactivators are the likely “master regula- for the same primary sequence protein. A “dif- tors” of our genome, capable of coordinately ferentially coded” coactivator is now predis- activating subgroups of genes that are required posed to form different multimeric coactivator for specific physiologic processes such as repro- complexes, and, thereby, is directed to interact duction, growth, inflammation, or metabolism with distinct genes and to perform different (O’Malley 2007). DNA-binding transcription compartmental functions in a cell. For example, factors, such as NRs, bind nearby to genes and over 40 separate modifications of the SRC-3 mark them for activation or repression, func- coactivator have been determined to date. In tions subsequently affected by the recruitment total, this plethora of PTMs creates an enor- of the coregulators. The coregulators exist and mous combinatorial “potential” of (2)40 for function in large multiprotein complexes that SRC-3. This vast PTM “potential complexity” are recruited by NRs to target genes in an likely is never fully used in cells of an animal. ordered sequence to provide the many enzyme Nevertheless, it can be speculated that every sin- capacities required for modifying histones and gle PTM on a protein results in a modified mol- other coactivational proteins for transcription ecule with “some” altered function. Thus, it is (Fig. 6). Subreactions of transcription mediated an inescapable conclusion that multiple combi- by coactivator complexes include chromatin nations of PTMs can bestow a huge array of modification and remodeling, initiation of distinct and diverse functions to any one core- transcription, elongation of RNA chains, gulator protein. mRNA splicing, and even, degradation of the Together with SRC-1 and SRC-2 (GRIP1/ activated NR-coregulator complexes and termi- TIF2), SRC-3 (AIB1/ACTR/RAC3/pCIP/ nation of the transcriptional response (Lonard TRAM1) completes the structurally related and O’Malley 2007). Surprisingly, recent re- p160 family of coactivator proteins, whose car- ports show that coactivators even can influence boxy-terminal domains mediate interactions cellular reactions outside the nucleus such as with histone acetyltransferases and the coregula- mRNA translation, mitochondrial function, tors CBP and p300, whereas the amino-terminal and cell motility. basic helix-loop-helix/PAS-containing domains When considering the plethora of functions interact with additional co-coregulators such as that NRs play in tissues, it is not surprising that CoCoA (coiled-coil coactivator, GAC63 (Grip1- a relatively large number of coregulators appear associated coactivator 63 and CARM1 (Coacti- to be involved in human breast cancer. The vator-associated arginine methyltransferase 1. cellular concentrations of coactivators and cor- SRC-3 activation and interactions with co-core- epressors are critical to their functional poten- gulators are initiated by posttranslational phos- tial. A high concentration of a coactivator will phorylations, whereby different combinations of lead to an amplified signal within a downstream site-specific phosphorylations provide inter- action pathway, as well as a action specificity for different co-coregulators much faster response to environmental signals. and transcription factors. However, available data suggest that the key to understanding the true diversity of coregulator Regulation of Coregulator Concentration functions lies in first understanding the surpris- and Activity ingly extensive “posttranslational coding” that has been discovered to exist in the coregulator Ubiquitinylation is another posttranslational proteins (Han et al. 2009). Such posttransla- modification that is essential for the regulation tional modifications (PTMs) include but are of SRC-3 by cellular signaling. It was recently not limited to phosphorylation, methylation, demonstrated that transcriptional activation

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Hormone Action

Histon acetylation RNA elongation mRNA splicing and initiation Degradation/termination CAPER CARM P/CAF TRAPs CoAA SRC E3 Ligases CBP/p300 SRC pTEFb ASC-2 ALR SRC

BRG/Brm

GTFs Chromatin Pre-mRNA remodeling TAFs H H RNA Pol II NR NR TBP Ac Me Capping RNA Pol II Ac Me Elongation Ac Me Termination

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.

and turnover of SRC-3 are events controlled by serine/threonine-P bonds to induce conforma- phosphorylation-dependent mono-ubiquitiny- tional changes in the SRC-3 protein and lation, which first super-activates the molecule enhance the interactions between SRC-3 and for specific gene transcriptional enhancement. other coactivators such as CBP/p300. In con- Ultimately, however, the transition from mono- trast, CARM1 methylates SRC-3 and dissociates ubiquitinylation to long-chain polyubiquiti- it from its active coactivator complex. nylation leads to SRC-3 degradation. Because Importantly, a recent study demonstrated the course of polyubiquitinylation is proces- that a previously undiscovered isoform of sive during the transcriptional activation of SRC-3 that lacks the amino-terminal nuclear transcription factors, this “phosphorylation- localization signal is produced from the SRC-3 dependent ubiquitinylation” functions as a (NCoA3) gene. This cytoplasmic isoform, is “transcriptional time clock” to first provide phosphorylated and activated by the PAK-1 activation, and then to ultimately limit the life- (p21 activated kinase) oncogenic kinase. time of the PTM-activated coactivator (Lonard When activated, this isoform, which lacks a and O’Malley 2008b). SRC-3 also is regulated by nuclear translocation signal, functions at the a posttranslational modification that influences cell membrane by interdigitating between the its structural association dynamics with other EGF receptor and FAK (focal adhesion kinase, co-coactivators. Peptidyl-prolyl isomerase 1 the main motility kinase of cells). In this way, (Pin1) catalyzes the cis/trans isomerization it acts as an adaptor to allow transduction of of proline residues adjacent to phosphorylated the signal for motility and invasion from the

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C. Brisken and B. O’Malley

EGFR (and Her2) receptor to the FAK enzyme. (Osborne et al. 2003). SRC-3, SRC-1, and other It is an impressive example of a nuclear coacti- coactivator proteins/genes are now being used vator gene integrating nuclear growth gene as markers for breast cancer prognosis and esti- responses (by full-length SRC-3) with a mem- mates of recurrence of disease after treatment brane growth signal (by the shorter isoform) (Redmond et al. 2009). for an important cellular response. This collab- oration has great pathologic impact in that the combination of SRC-3 gene overexpression CONCLUDING REMARKS and EGFR (Her2) overexpression is a deadly Powerful FACS sorting approaches and a grow- combination in human breast cancer, leading ing repertoire of markers for different cell pop- to early tamoxifen resistance and rapid progres- ulations within the mammary gland now allow sion of the disease (Long et al. 2010). the research community to explore the hitherto The oncogenic potential for coactivators is hidden organization of cells within different now generally accepted. Coactivators designed compartments of the mammary gland. Ever as “master regulators” for cell growth coordin- more powerful imaging techniques are used to ately regulate the expressions of many genes unravel interactions with immune cells when that must be in play simultaneously for effective not so long ago these were a black box. Major growth. SRC-3/AIB1 is over expressed in 40%– challenge remain in the manipulation of selec- 65% of human breast cancers and is amplified tive stromal components with first steps made in up to 10% of breast cancers; its cellular and with new Cre lines (Trimboli et al. 2008), and in vivo oncogenic activities have been demon- in understanding how the findings in the mouse strated in multiple labs. Tumorigenic activity model can be extrapolated to human beings. of SRC-3 is substantiated by studies in trans- Our appreciation of how mammary gland and genic mice that overexpress SRC-3 and develop breast cancer development are orchestrated by spontaneous malignant mammary tumors (Xu systemic hormones promises to continue to et al. 2009). In contrast, SRC-3 knockout mice evolve quickly. are resistant to chemical carcinogen-induced and viral-induced mammary tumorigenesis. SRC-3-/- mice also show resistance to induced ACKNOWLEDGMENTS prostate cancer progression. All of these results The authors thank F.Koerner for critical reading are consistent with the idea that SRC-3 is a of the manuscript. potentially powerful oncogene. In the lym- phatic system, however, SRC-3 can act para- doxically as a tumor suppressor because B-cell REFERENCES lymphomas develop in gene-deleted mice. Antal MC, Krust A, Chambon P,Mark M. 2008. Sterility and These two faces of SRC-3 highlight the fact absence of histopathological defects in nonreproductive that SRC-3 is a versatile protein, allowing the organs of a mouse ERbeta-null mutant. Proc Natl Acad cell to decide between proliferation or growth Sci 105: 2433–2438. suppression in a cell and signal context- Antuna-Puente B, Feve B, Fellahi S, Bastard JP.2008. Adipo- kines: The missing link between resistance and dependent manner. Although the majority of obesity. Diabetes Metab 34: 2–11. studies have been directed toward SRC-3, Aupperlee MD, Smith KT, Kariagina A, Haslam SZ. 2005. SRC-1 and SRC-2 are not without relevance to isoforms A and B: Temporal and cancer. SRC-1 has been shown to be necessary spatial differences in expression during murine mam- mary gland development. Endocrinology 146: 3577– for tumor metastasis in mice and has been 3588. suggested as a reliable marker for disease reoc- Bachelot A, Binart N. 2007. Reproductive role of prolactin. currence in human breast cancer. The combina- Reproduction 133: 361–369. tion of overexpression of SRC-3 and Her2 is Bern HA, Mills KT,Jones A. 1983. Critical period for neona- tal estrogen exposure in occurrence of mammary gland deadly, producing early tamoxifen resistance abnormalities in adult mice. Proc Soc Exp Biol Med 172: and rapid progression to death for patients 239–242.

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Hormone Action in the Mammary Gland

Cathrin Brisken and Bert O'Malley

Cold Spring Harb Perspect Biol 2010; doi: 10.1101/cshperspect.a003178 originally published online August 25, 2010

Subject Collection The Mammary Gland as an Experimental Model

On the Role of the Microenvironment in Mammary On How Mammary Gland Reprogramming Gland Development and Cancer Metalloproteinases Couple Form with Function Derek Radisky Bonnie F. Sloane On Using Functional Genetics to Understand On Molecular Mechanisms Guiding Embryonic Breast Cancer Biology Mammary Gland Development Kornelia Polyak Gertraud W. Robinson On Oncogenes and Tumor Suppressor Genes in On Stem Cells in the Human Breast the Mammary Gland Mark A. LaBarge Rushika M. Perera and Nabeel Bardeesy On Leukocytes in Mammary Development and On Murine Mammary Epithelial Stem Cells: Cancer Discovery, Function, and Current Status Cyrus M. Ghajar Jeffrey M. Rosen On Chromatin Remodeling in Mammary Gland On In Vivo Imaging in Cancer Differentiation and Breast Tumorigenesis David Piwnica-Worms Kornelia Polyak On Hormone Action in the Mammary Gland Choosing a Mouse Model: Experimental Biology J.M. Rosen in Context−−The Utility and Limitations of Mouse Models of Breast Cancer Alexander D. Borowsky TGF-β Biology in Mammary Development and Mammary Gland ECM Remodeling, Stiffness, and Breast Cancer Mechanosignaling in Normal Development and Harold Moses and Mary Helen Barcellos-Hoff Tumor Progression Pepper Schedin and Patricia J. Keely A Compendium of the Mouse Mammary Tumor Molecular Mechanisms Guiding Embryonic Biologist: From the Initial Observations in the Mammary Gland Development House Mouse to the Development of Genetically Pamela Cowin and John Wysolmerski Engineered Mice Robert D. Cardiff and Nicholas Kenney For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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