foxa1 as a therapeutic target for breast cancer

Review

10.1517/14728222.11.4.507 © 2007 Informa UK Ltd ISSN 1472-8222 507

Oncologic, Endocrine & Metabolic

FOXA1 as a therapeutic target for breast cancerHarikrishna Nakshatri† & Sunil Badve†Indiana University School of Medicine, Departments of Surgery, Biochemistry and Molecular Biology, Walther Oncology Center, Indianapolis, IN 46202, USA

Gene expression profiling studies have classified breast cancer into fiveintrinsic subtypes with distinct prognostic significance: luminal type A,luminal type B, normal-like, HER-2-positive and basal type. These studieshave also uncovered novel diagnostic markers and molecular targets. FOXA1,a winged-helix transcription factor belonging to the forkhead family, is oneamong them as it is expressed predominantly in luminal type A breast cancer,which is characterized by the presence of estrogen receptor-α (ERα) withfavorable prognosis. FOXA1 is a ‘pioneer’ factor that binds to chromatinizedDNA, opens the chromatin and enhances binding of ERα to its target genes.It is essential for the expression of ∼ 50% of ERα:estrogen-regulated genes.Thus, a network comprising FOXA1, ERα and estrogen constitutes a majorproliferation and survival signal for luminal type A breast cancer. However, bycontrolling differentiation and by regulating the expression of cell cycleinhibitor p27kip1 and the cell adhesion molecule E-cadherin, FOXA1 mayprevent metastatic progression of luminal type A breast cancer. This articlereviews possible roles of FOXA family transcription factors in breast cancerinitiation, hormone dependency and speculates on the potential of FOXA1 asa therapeutic target.

Keywords: breast cancer, estrogen receptor, FOXA1, luminal type A

Expert Opin. Ther. Targets (2007) 11(4):507-514

1. Introduction

Breast cancer is one of the most common cancers, affecting 12% of women in thewestern world. Recent advances in the understanding of molecular pathwaysassociated with cancer progression have allowed development of targeted therapies forspecific subtypes of breast cancers [1]. One such example is trastuzumab, which tar-gets the HER2 pathway and is beneficial only for patients with HER2-overexpressingtumors [2]. Despite success with trastuzumab, targeted therapies or therapies tailoredfor individual patients, for the majority of breast cancers, are yet to be developed.This can become a reality once novel functional biomarkers/signaling pathways,which are absolutely critical for proliferation and survival of cancer cells, can bereliably identified for individual cancers using simple assays.

Breast cancers are broadly classified into estrogen receptor-α (ERα)-positive andERα-negative [3]. Patients with ERα-positive breast cancers usually have better prog-nosis, which is partly due to their response to endocrine therapy. Recent geneexpression profiling studies enabled further classification of breast cancers into fiveintrinsic subtypes with variable prognostic significance: luminal type A, luminaltype B, ERα-negative/HER2-positive, normal-like and basal type (Figure 1) [4].Both luminal type A and luminal type B breast cancers are ERα-positive withluminal type A expressing higher levels of ERα and showing better prognosis [4]. Atpresent, it is not clear whether intrinsic subtype classification of breast cancers issimply a prognostic classification or if it reflects cell-lineage specific origin of breast

1. Introduction

2. Forkhead family transcription

factors involved in development

and metabolism

3. FOXA subfamily and

transcription

4. FOXA and nuclear receptors

5. FOXA and cancer

6. FOXA1 as a marker for luminal

subtype A breast cancer

7. FOXA1: is it a therapeutic target

for breast cancer?

8. Expert opinion and conclusion

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FOXA1 as a therapeutic target for breast cancer

508 Expert Opin. Ther. Targets (2007) 11(4)

cancer, with each subtype being critically dependent onunique signaling pathways for proliferation and survival. It islikely that some of the genes that are uniquely expressed in anintrinsic subtype are part of the signaling network that controlproliferation and/or survival of cancer cells and, hence, aretargets for drug development. For example, ERα activity isessential for proliferation of ERα-positive and, therefore, maybe essential for survival of luminal type A breast cancers. Inaddition, cofactors that work in concert with ERα and arerequired for optimum activity of ERα may be essential forluminal type A breast cancers. Such cofactors are additionaltargets for drug development for luminal type A breast cancer.Recent studies have identified FOXA1, a member ofForkhead family transcription factors [5], as a ‘pioneer factor’required for the function of ERα [6,7]. Therefore, FOXA1 is atarget for luminal type A breast cancer, which is the focus ofthis article.

2. Forkhead family transcription factors involved in development and metabolism

The term ‘Forkhead’ originated from studies involvingfounding members of this family in Drosophila [8]. TheDrosophila forkhead was identified in a screen ofembryonic-lethal mutations that gave rise to ectopic headstructures (or ‘fork head’) [9]. Since then, > 100 evolutionarilyconserved members of this family have been identified [5].The unique feature of this family is the presence of a‘forkhead’ box (FOX) that binds DNA. This unique DNAbinding domain located at the center of the protein consists ofthree α-helices and two large loops or wings, which appearslike a butterfly in crystal structure [10]. Therefore, the DNAbinding domain is also named as winged helix DNA bindingdomain. Members of this family bind DNA as monomers andactivate or repress gene expression. The N terminus and

Figure 1. Classification of breast cancer to intrinsic subtype. Sorlie et al. [4] classified breast cancers to intrinsic subtypes based onmicroarray analysis. Note FOXA1 expression in luminal type A breast cancers.ER: Estrogen receptor.

BREAST CANCER

Intrinsic subtypes

ERα +

Luminal subtype A Luminal subtype B + C

High ER expressionGATA3X-box binding proteinFOXA1LIV

p53 mutation 13%5-year survival ∼ 90%

Low to moderate ER

p53 mutation 40%5-year survival 50%

Novel genes ofunknown functionTransferrin receptorV-myb oncogenehomolog


Normal breast-like

Adipose and otherepithelial markersLipoprotein lipase Integrin α7


ErbB2(her2/neu)

ErbB2Grb7

p53 mutation 71%

5-year survival 30%

Basal-like

Troponin 1Gro1 oncogeneCytokine family

p53 mutation 82%

5-year survival < 10%

ERα -

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Expert Opin. Ther. Targets (2007) 11(4) 509

C terminus contain transactivation domains (two each) and itis likely that the function of these domains is regulated at thelevel of phosphorylation [11]. Based on phylogenic analysis,this family has been further classified into 17 subfamilies(FOXA to FOXQ in human) [5,101]. These genes are involvedin varied cellular processes including differentiation (FOXA),metabolism (FOXA), initiation of liver development (FOXA1and FOXA2), apoptosis (FOXO), epithelial cell proliferation(FOXF), cell cycle regulation and senescence (FOXM),immune function and tolerance (FOXN and FOXP) andstem/progenitor cell functions (FOXD) [12-21].

3. FOXA subfamily and transcription

FOXA1, also called hepatocyte nuclear factor 3α (HNF3α),is the founding member of this subfamily and was identifiedas a hepatocyte enriched transcription factor that is requiredfor the expression of transthyretin and α1-antitrypsingene [8,22,23]. Two additional members, FOXA2 (HNF3β)and FOXA3 (HNF3γ), were subsequently identified [8]. Theybind to TGTTTGPy or TGTTTGCT motifs present in thepromoter/enhancer regions of target genes with variableaffinity and modulate transcription [24,25]. Although thesegenes show a unique tissue-specific expression pattern, theycompete for the same binding sites in tissues where they arecoexpressed [26]. Single deletion of FOXA1, FOXA2 orFOXA3 did not prevent the establishment of competence inthe foregut endothelium or hepatic development in mice,suggesting that they can compensate for the loss of one familymember [14]. However, deletion of all of them resulted incomplete loss of hepatic development [14]. In contrast, inembryonic stem cells, FOXA2 is more potent than FOX1 ininducing endoderm differentiation [27]. Thus, depending ontissues, FOXA1 and FOXA2 may perform redundant andnon-redundant functions. It is interesting that FOXA2, butnot FOXA1, is phosphorylated by AKT, which results innuclear exclusion [28]. Thus, apart from tissue-specific differ-ences in the expression pattern, extracellular signals maydifferentially regulate the activity of FOXA family members.

Transcription in eukaryotes occurs in the context of DNAorganized into chromatin and remodeling of the compactedchromatin is one of the initial steps in transcription [29]. DNAis usually wrapped around a histone octamer containing twoof each of the core histones H2A, H2B, H3 and H4 to form anucleosome. Nucleosomes are further compacted by linkerhistones, such as histone H1 and histone H5. Severaltranscription factors recruit co-activator molecules withvarious enzymatic activities that would allow them to modifychromatin [29]. However, a question that remained untilrecently is how transcription factors bind to compactedchromatin in the first place; compacted chromatin is notconducive to such interactions. In this regard, the FOXAfamily has emerged as a unique class of transcription factorsthat can bind to compacted chromatin [30]. The DNAbinding domain of FOXA is structurally similar to histone

H5, whereas its C-terminus interacts with histone H3 andH4 [10,30]. These structural features allow FOXA to bind com-pacted chromatin and to open the local nucleosomal domainin the absence of other chromatin modifying enzymes. Bydoing so, FOXA enhances the recruitment of other transcrip-tion factors to chromatin, which leads to further opening ofthe chromatin through transcription factor-associatedATP-dependent enzymes. Because of these properties, FOXAis dubbed as ‘pioneer factor’ [30,31]. As discussed in Section 4,some of the nuclear receptors, which bind DNA only in thepresence of their ligands, use this function of FOXA to gainaccess to their binding sites in chromatinized templates.Within this context, FOXA gained attention of cancerbiologists studying hormonally regulated cancers.

4. FOXA and nuclear receptors

Nuclear receptor superfamily transcription factors arecharacterized by the presence of unique zinc-finger containingDNA binding domain and a ligand binding domain [32]. Theyare further classified into steroid and non-steroid receptors.A major difference between steroid and non-steroid receptorsis that ligand-induced conformational change potentiatesDNA binding of steroid receptors whereas several of thenon-steroid nuclear receptors bind DNA in the absence of theligand. ERα, progesterone receptor (PR), glucocorticoidreceptor (GR), androgen receptor (AR) and mineralocorticoidreceptor (MR) belong to the steroid receptor subfamily.Factors that facilitate DNA binding of liganded steroidreceptor to chromatinized DNA in vivo were not known untilrecently. Advances in techniques that contributed to mappingof ERα binding sites in chromosomes revealed a specific rolefor FOXA1 in the recruitment of ERα to ∼ 50% to targetgenes [6,7,33]. In fact, FOXA1 is essential for ERα-estrogeninducible expression of these genes. Although studies with ARand GR are not as extensive as ERα, genes that are regulatedby AR and GR also contain FOXA binding sites [34,35]

and absence of FOXA2 in vivo affects GR binding to itstargets [36]. A schematic view of how FOXA may enhanceERα function is shown in Figure 2. Additional studies arerequired to pronounce FOXA as ‘pioneer factor’ required forthe function of all steroid receptors.

5. FOXA and cancer

Breast and prostate cancers are the two major cancers that areinfluenced by hormones. Considering an established role ofFOXA in the regulation of ER and AR function, it is notsurprising to observe expression of FOXA in ERα-positivebreast cancers and AR-positive prostate cancers [4,37]. A smallfraction of ERα-negative breast cancers that express AR alsoexpress FOXA1 [38]. In normal prostate, FOXA1 is essentialfor differentiation of epithelial cells as prostate of FOXA1knockout mice show hyperplastic lesions, which is compatiblewith basal cell hyperplasia [13,37]. Similar studies with

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mammary gland of FOXA1 knockout animals are yet tobe published. In prostate tumors, FOXA1 expression wasalways observed regardless of Gleason grade and is notupregulated [37]. In contrast, FOXA2 is overexpressed ininvasive carcinoma containing neuroendocrine features.Although FOXA1 and FOXA2 are involved in pancreaticdevelopment, expression status of these genes in this cancer isyet to be determined [8]. FOXA1 expression is not altered inanimal models of hepatocellular carcinoma, whereas FOXA3is downregulated in these cancers [39]. Amplification and/oroverexpression of FOXA1 are observed in lung (37%) andesophageal (6.7%) cancers [40]. Recent studies have suggesteda role for ERα and ERβ in lung cancer progression [41-43].Whether or not overexpressed FOXA1 cooperates with thesereceptors in promoting hormone-dependent proliferation oflung cancer remains to be determined.

6. FOXA1 as a marker for luminal subtype A breast cancer

FOXA1 is expressed mostly in breast cancer cell linesthat express ERα and cDNA microarray cluster analysissegregates FOXA1 with genes that characterize luminal type Asubtype such as ERα, GATA-3 and X-box-binding protein

(XBP)-1 [4,44,45] (C Perou, pers. commun.). Studies involvingmice with mammary-specific deletion of GATA-3 have revealeda functional link between ERα, GATA-3 and FOXA1 in differ-entiation of luminal cells, which supports microarray analysisshowing clustering of ERα, FOXA1 and GATA-3 to a specificintrinsic subtype of breast cancer [46]. Recent assignment ofFOXA1 as a pioneer factor required for the expression of amajority of estrogen-inducible genes further suggested a role forthe ERα–estrogen–FOXA1–GATA-3 axis in initiation and/orprogression of luminal type A breast cancers [31]. To furtherconfirm the association of FOXA1 and ERα at protein levelswith luminal type A breast cancers and to link this associationwith survival, the authors recently performed tissue microarrayanalysis involving 438 patients with 20-year follow-up.Remarkably, FOXA1 expression correlated with ERα-positivityand luminal type A phenotype [47]. Moreover, consistent withmicroarray data showing better prognosis of patients withluminal type A breast cancer [4], FOXA1 expression wasassociated with good prognosis. It is likely that luminal type Abreast cancers are more responsive to antiestrogen treatmentthan other types of breast cancers because these cancers aredependent on estrogen for proliferation and survival. This is inmarked contrast to luminal type B breast cancers, which,although being ERα-positive, are associated with poor

Figure 2. Role of FOXA1 in ERα function. Binding of FOXA1 to ERα target genes may facilitate opening of compacted chromatin,which allows efficient DNA binding of liganded ERα. Unliganded ERα is complexed with co-repressors, whereas liganded ERα isassociated with co-activators. Phosphorylation of ERα leads to changes in co-activator and co-repressor interaction. ERα binds toconsensus ER response elements as dimers. For simplicity, only monomer binding is shown in the figure.AF-1: Activation function 1; AF-2: Activation function 2; CBP: CREB binding protein; CoA: Co-activator; CoR: Co-repressor; DBD: DNA binding domain; E2: Estrogen;ERα: Estrogen receptor-α; Pho: Phosphorylation; RNA Pol II: RNA polymerase II.

Inactive

ERα

Co-activators (CoA)

p160 family

CBP/p300

Co-repressors (CoR)

NCoR

SMRT

DBD

Pho E2PhoPho E2

CoR

Chromatin condensation Decondensation

Transactivation

E2 orphosphorylation

Active ERα

DBD

FOXA1

RNA Pol IIFOXA1

AF-1

AF-1

AF-2

AF-2

CoA

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prognosis. Luminal type B cancers may possess redundantsurvival/proliferation pathways, one mediated by ERα:E2 andthe other mediated by growth factor receptors, includingepidermal growth factor receptor (EGFR) and HER2. In vitrostudies using ERα-positive/HER2-positive breast cancer cell lineBT474 provides some evidence for such a possibility [48]. BT474cells that have become resistant to lapatinib, an inhibitor of bothEGFR and HER2, acquire an ERα-dependent survival pathway.It is possible that lapatinib-resistant BT474 behave in a similarway to luminal type A cells. Although luminal type A andluminal type B breast cancers are believed to be intrinsicallydifferent [4], whether or not luminal type A breast cancersacquire some of the proliferation/survival properties of luminaltype B breast cancers when they progress fromantiestrogen-sensitive to antiestrogen-resistant phenotype is notknown. Breast cancers that initially respond to the antiestrogentamoxifen but subsequently acquire resistance, often showelevated crosstalk between ERα and growth factor signaling thatenables them to grow independent of estrogen [49]. To whatextent FOXA1 expression and/or activity are affected during thisprogression of luminal type A to antiestrogen resistance is notknown. The authors predict that FOXA1 will emerge as areliable marker to assess progression of luminal type A cancerswith properties similar to luminal type B as outlined in Figure 3.

7. FOXA1: is it a therapeutic target for breast cancer?

The association of FOXA1 expression with good prognosisand its ability to promote estrogen-dependent proliferation

suggests a dual role for this protein in breast cancer; tumorpromoter at initial stages, but tumor suppressor in later stages.In the normal breast, only 5 – 10% of cells express ERα andthese are non-dividing cells [50]. However, > 50% of breastcancers are ERα-positive and these cancers are dependent onestrogen for proliferation and survival. Does a signalingpathway that enhances the activity of FOXA1 towards ERα,but simultaneously inhibit its ability to induce differentiation,convert non-dividing ERα-positive cells to proliferating cellsby changing DNA binding pattern of ERα? If that is the case,FOXA1 can be considered as a primary gene involved ininitiation of ERα-positive breast cancers and inhibiting itsactivity may help to prevent luminal type A breast cancer. Incontrast, if ERα-positive breast cancers initiate independentof FOXA1 and the primary role of FOXA1 is to imposeestrogen dependency to these cancers after having failed toinduce differentiation of these cells due to transformationevents, then elevating FOXA1 expression may preventluminal type A cancers from progressing into theestrogen-independent growth phenotype. Based on results ofdifferentiation defects in prostate epithelial cells in FoxA1-/-

mice [13] and from results of studies with BT474 cells [48], theauthors favor the later possibility. It is also interesting thatFOXA1 regulates that expression of p27kip1 and E-cadherin,which are known to prevent progression of breast cancers tometastatic phenotype [51,52]. The authors believe drugs thatenhance the activity/expression of FOXA1 may help tomaintain ERα-positive tumors dependent on estrogen forsurvival and prevent their metastatic progression, andcombining these drugs with antiestrogens may help to prevent

Figure 3. A model depicting FOXA1-dependent phenotypic changes in luminal type A and luminal type B breast cancers.Intrinsic differences between luminal type A and luminal type B breast cancers may be attributed to FOXA1 expression and/or activity.Whether enforced expression of FOXA1 in luminal type B cells leads to phenotypic changes similar to that of luminal type A is not known.E2: Estrogen; EGFR: Epidermal growth factor receptor; ERα: Estrogen receptor-α.

Luminal type AERα+

FOXA1+

Loss/reduction of FOXA1 expression?Luminal type BERα+

EGFR or Her2+

Two redundant survival/proliferation

pathways; E2 or growth factors

Non-responsive to antiestrogens

May be responsive to both

antiestrogens and growth factor

receptor antagonists

Activation of FOXA1?

Dependent on E2 forsurvival/proliferation

Responsive to antiestrogens

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progression of these tumors to estrogen independence. Asmice with homozygous deletion of FoxA1 gene die during thefirst two weeks of postnatal development [53], additional studiesin animal models that involve mammary-specific deletion ofFoxA1 and transgenic mice that develop ERα-positive tumors(mouse mammary tumor virus-polyoma middle T antigen[MMTV-PyMT] or p53-/- model) [54,55] may help to resolvethis issue. If FOXA1 is required for initiation of ERα-positivetumors, MMTV-PyMT or p53-/- mice in mammary-specificFoxA1 knockout background should not develop ERα-positivetumors. In contrast, if FOXA1 prevents progression of tumorsto ERα-negative phenotype, MMTV-PyMT or p53-/- mice inFoxA1-/- (mammary-specific) background should developaggressive ERα:estrogen-independent tumors. In this regard,mammary-specific deletion of GATA-3, which regulatesFOXA1 expression, leads to expansion of luminalprogenitor cells at the expense of differentiated alveolar andductal epithelial cells [56]. It is possible that FOXA1 mediatessome of the effects of GATA-3 and loss of FOXA1 expressionin the mammary gland may have an effect on luminalprogenitor pool.

8. Expert opinion and conclusion

Recent technological breakthroughs (microarrays andChiP-on-chip, for example) combined with gold standardtechniques such as immunohistochemistry have enabledclassification of breast cancers to distinct subtypes with uniqueprognostic significance. The same approach has also helped toidentify novel targets; FOXA1 is one among them. Althoughat outset, anything that increases ERα activity can be consid-ered to have a negative role in breast cancer, FOXA1 does notappear to fall into that category. It is the authors’ opinion that

FOXA1 may force ERα-positive breast cancers to bedependent on estrogen for survival and such cancers can thenbe susceptible for antiestrogens. Also, by increasing the expres-sion of E-cadherin, FOXA1 may prevent epithelial to mesen-chymal transition and reduce motility. Agents that increase ormaintain FOXA1 expression may, therefore, be beneficial forERα-positive breast cancers. In this regard, FOXA1 is a retin-oic acid inducible protein and retinoic acid has been shown toinhibit the growth of mostly ERα-positive breast cancercells [57,58]. Moreover, liarozole fumarate, an inhibitor ofretinoic acid metabolism, has been shown to have some effecton ERα-positive/tamoxifen-resistant patients in Phase IIclinical trials [59]. Insulin, in contrast, has been shown toinhibit FOXA1 expression [26]. Although there is a definiteassociation between elevated circulating levels of insulin-likegrowth factor 1 (IGF-1) and antiestrogen resistance [60], it isnot known whether or not insulin and IGF-1 force progressionof luminal type A cells to cancers with some of the propertiesof luminal type B breast cancers by reducing FOXA1 expres-sion. Relationship between FOXA2 and FOXA3 and breastcancer has not been explored and it may be another importantarea as both FOXA2 and FOXA3 can alter the function ofFOXA1. In conclusion, the authors’ believe that FOXA1 is notjust a good prognostic marker for breast cancer but also is atarget for therapy. Unlike many other targets, drugs that pre-vent loss of FOXA1 expression or elevate FOXA1 expressionmay help to prevent or delay breast cancer from progressingfrom a good prognosis group to a bad prognosis group.

Acknowledgements

Work in Nakshatri’s lab is supported in part by the grant fromthe National Institutes of Health (R01 CA89153).

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Website

101. http://www.biology.pomona.edu/fox.htmlWinged helix proteins (2007).

AffiliationHarikrishna Nakshatri†1 BVSc, PhD & Sunil Badve2 MBBS, MD, FRCPath†Author for correspondence1Associate Professor and Marian J Morrison Investigator in Breast Cancer Research, Indiana University School of Medicine, Departments of Surgery, Biochemistry and Molecular Biology, Walther Oncology Center, Indianapolis, IN 46202, USAE-mail: [email protected] Professor, Indiana University School of Medicine, Departments of Pathology and Internal Medicine, Indianapolis, IN 46202, USA

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foxa1 as a therapeutic target for breast cancer

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