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Diseases of the Breast
Estrogen and Progesterone Receptors
Richard M. Elledge and Suzanne A. W. Fuqua

R. M. Elledge: Breast Care Center, Departments of Medicine and Oncology, Baylor College of Medicine, Houston, Texas
S. A. W. Fuqua: Department of Medicine, Baylor College of Medicine, Houston, Texas

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Introduction
Organizational Structure
Structure-Function Relationship
New Estrogen Receptor Subtype—Estrogen Receptor b
Nuclear Receptor Coregulatory Proteins
Selective Estrogen-Receptor Modulators
Alternative Signaling of The Estrogen Receptor and Estrogen Independence
Genomic Alterations Of Estrogen Receptor a in Breast Cancer
Potential Relevance of Variant Estrogen Receptor a Isoforms
Variant Estrogen Receptor b Isoforms
Importance of Receptors in Clinical Breast Cancer
Methods of Measuring Estrogen and Progesterone Receptors
 
Ligand-Binding Methods
 
Assays Using Monoclonal Antibodies
 
Comparison of Assay Methods
Estrogen and Progesterone Receptors in the Clinical Management of Breast Cancer Patients
 
Use of Estrogen-Receptor and Progesterone-Receptor Status to Predict Response to Hormone Therapy in Advanced Disease
 
Use of Estrogen-Receptor and Progesterone-Receptor Status to Predict Response to Adjuvant Therapy
 
Responses in Patients with Estrogen Receptor–Negative Tumors
 
Definition of Cutoffs for Receptor Status
 
Estrogen-Receptor and Progesterone-Receptor Status as Prognostic Factors
Conclusion
Chapter References

INTRODUCTION
The powerful, probing tools of molecular biology now enable us to see further and deeper into the cellular universe of breast cancer, greatly expanding the horizons of knowledge and understanding. Still, in the center of this complex and vast molecular space, steroid receptors remain, playing important and crucial roles in the basic biology of the disease and also illuminating the pathways involved in the clinical management and treatment of women with breast cancer.
In the early 1960s, radiolabeled estrogens were first observed to be preferentially concentrated in the estrogen target organs of animals and also in human breast cancers—observations that gave rise to the concept of an “estrogen receptor.”1,2 and 3 Since then, it has become clear that human breast cancers are dependent on estrogen or progesterone, or both, for growth. This stimulatory effect is mediated through the estrogen receptor (ER) and progesterone receptor (PR). Probably not coincidentally, both are found relatively overexpressed in most malignant breast tissue. The concept of targeting therapy toward molecular components preferentially overexpressed by breast cancer cells has become a popular one4,5; more than 100 years ago, however, the ER was the therapeutic target for the first breast cancer systemic therapy, hormonal manipulation.6 The usefulness of targeting the receptor has clearly stood the test of time,7 something that cannot yet be said of the most recent contenders.
New insights into the biology of the ER and the wide array of coregulatory proteins that can modify its function have already begun to lead to better therapies. In the clinic, the number of available drugs that interact with the receptor, drugs that are sometimes called selective estrogen-receptor modulators (SERMs), grows steadily each year. Along with this, methods for assaying receptor proteins have led to less expensive, simpler, and possibly more accurate measurements of ER and PR for clinical use. This chapter reviews the structural and mechanistic biology of ER and PR, especially as it relates to therapy, discusses current methods for measuring ER and PR for clinical use, and presents evidence that supports the usefulness of ER and PR in assessing clinical outcome and selecting therapy.
ORGANIZATIONAL STRUCTURE
The ER and PR belong to a superfamily of nuclear hormone receptors that, in addition to several other steroid hormone receptors, also includes thyroid hormone, vitamin D, and retinoic acid receptors. These receptor proteins function as transcription factors when they are bound to their respective ligands. Since the original cloning of complementary DNAs (cDNAs) for ER8,9 and PR,10 an explosion of information has occurred in the field of steroid hormone action. These receptors share a common structural and functional organization; their functional domains have been designated A through F (Fig. 31-1). Classic ER (now called ERa) contains 595 amino acids with a central DNA-binding domain, along with a carboxy-terminal hormone-binding domain. Binding of hormone to the ER facilitates the activation of the receptor with the coincident disassociation of chaperone proteins, such as heat shock protein 90. Hormone-bound ER then dimerizes and binds to the estrogen response elements present in the promoter of estrogen-responsive genes. ER is also complexed with a number of coregulatory proteins that coordinately act to influence the transcription of estrogen-responsive genes.

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FIG. 1. Schematic diagram of estrogen receptor a functional domains. The ER contains 595 amino acids (aa) with the functional domains labeled A through F and a central DNA-binding domain (DBD) and hormone-binding domain (HBD). The regions important for dimerization (Dimer) and transactivation functions (AF-1, AF-2a, AF-2) are shown. Region A/B is important for hormone-independent ER transcription; region C is the DBD; region D is the hinge domain; region E is the HBD responsible for hormone-dependent transcription; region F is important for modulation of ER activity.

STRUCTURE-FUNCTION RELATIONSHIP
On estrogen binding, the ER forms homodimers and binds to DNA through its DNA-binding domain (DBD) (see Fig. 31-1, region C) with high affinity at specific sites termed estrogen-responsive elements (EREs).11,12 The DNA-binding domain contains eight cysteine residues that are arranged in two zinc-finger motifs, each of which is followed by an extended a helix.13 EREs have classically been viewed as two inverted, palindromic half-sites of the sequence GGTCA separated by three variant nucleotides. Of interest is the discovery that novel sequences containing restricted homology to the canonical ERE half-site can function as EREs in mammalian cells,14 thus enlarging the number ofgenes that potentially are regulated by estrogen. The crystal structure of the ER has also been solved as a complex with DNA,15 and this structure confirmed the models of the DNA-binding domain developed from models predicted from mutational analysis.12,16
Through DNA binding, the ER influences the expression of estrogen-responsive genes, such as the PR, which are important in mitogenic signaling, and their transcription is stimulated through at least two distinct transactivation domains located in the amino-terminal A/B region (AF-1) and the carboxy-terminal E region of the receptor (AF-2).17,18 and 19 These two ER regions appear to act in concert to promote full transcriptional ctivation of estrogen-responsive genes. The genomic organization of the human ER gene is quite complex; eight exons span more than 140 kilobase pairs of DNA.20 The two ER transcriptional activation domains are not encoded within single exons but rather encompass large regions of the receptor. A hormone-independent, amino-terminal ER activation domain is contained within exons 1 and 2 and is termed AF-1. A hormone-dependent, carboxy-terminal activation domain is contained within portions of exons 4 through 8 and is termed AF-2.21 A region exists within AF-2 that is highly conserved among nuclear hormone receptors and is composed of hydrophobic and charged residues critically important for hormone-dependent transcriptional activation.22
A third activation domain has been identified in the human ER within the amino-terminal part of AF-2 that has been designated AF-2a23 (see Fig. 31-1). This region has either a constitutive transcriptional activating function or, alternatively, a stimulatory effect on AF-1. In addition, just downstream of the AF-2a domain is a negatively acting domain.23 This region is also involved in binding of heat shock protein 90, a process that modulates receptor activation.24 Similarly, a third potential activation domain has been mapped within the amino-terminus of the B form of the PR.25 Thus, the steroid receptor transactivation domains appear numerous and more complex than previously appreciated, and further work is required to completely delineate the various regions important for different transcriptional activating functions on specific genes.
Both AF-1 and AF-2 are required for maximal ER transcriptional activity in most cellular environments26; both cellular and promoter contexts are important for determining transcriptional activity.27 On certain promoters, AF-1 and AF-2 can function independently.26 Research has now determined that, when AF-2 is required for ER transcriptional activity, antiestrogens such as tamoxifen (tamoxifen citrate) function as pure antagonists. However, in cellular contexts in which AF-2 is not required and AF-1 is sufficient for ER transcriptional activity, then tamoxifen can function as a partial agonist.26,28 Therefore, antiestrogens can behave as AF-2 antagonists and AF-1 agonists. The fact that antiestrogens interact differentially with these two transactivational domains depending on the cellular environment may explain why, in the clinic, these molecules can function both as antagonists in breast tissue and as ER agonists in the uterus, bone, and cardiovascular system.

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