Estrogen receptor alpha

Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein^[5]) that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1 (EStrogen Receptor 1).^[6][7][8]

Structure

The estrogen receptor (ER) is a

• Endogenous estrogens (e.g., estradiol, estrone, estriol, estetrol
  )
• conjugated equine estrogens
  )
• Synthetic estrogens (e.g., ethinylestradiol, diethylstilbestrol
  )

• Propylpyrazoletriol (PPT)
• 16α-LE₂ (Cpd1471)
• 16α-IE₂
• ERA-63 (ORG-37663)
• full agonist
• (R,R)-Tetrahydrochrysene ((R,R)-THC) – actually not selective over ERβ, but rather an antagonist instead of an agonist of ERβ

Mixed

• Phytoestrogens (e.g., coumestrol, daidzein, genistein, miroestrol)
• Selective estrogen receptor modulators (e.g., tamoxifen, clomifene, raloxifene)

Antagonists

Non-selective

• Antiestrogens (e.g., fulvestrant, ICI-164384, ethamoxytriphetol)

Selective

Antagonists of ERα selective over ERβ include:

• Methylpiperidinopyrazole (MPP)

Affinities

Tissue distribution and function

ERα plays a role in the physiological development and function of a variety of

ERα is essential in the maturation of the female reproductive phenotype. In the absence of ERα, the ERKO mouse develops an adult uterus, indicating that ERα may not mediate the initial growth of the uterus.^[12][13] However, ERα plays a role in the completion of this development, and the subsequent function of the tissue.^[15] Activation of ERα is known to trigger cell proliferation in the uterus.^[14] The uterus of female ERKO mice is hypoplastic, suggesting that ERα mediates mitosis and differentiation in the uterus in response to estrogen stimulation.^[13]

Similarly,

Estrogen stimulation of ERα is known to stimulate cell proliferation in breast tissue.^[14] ERα is thought to be responsible for pubertal development of the adult phenotype, through mediation of mammary gland response to estrogens.^[15] This role is consistent with the abnormalities of female ERKO mice: the epithelial ducts of female ERKO mice fail to grow beyond their pre-pubertal length, and lactational structures do not develop.^[13] As a result, the functions of the mammary gland—including both lactation and release of prolactin—are greatly impaired in ERKO mice.^[15]

Bone

Though its expression in bone is moderate, ERα is known to be responsible for maintenance of bone integrity.^[14][15] It is hypothesized that estrogen stimulation of ERα may trigger the release of growth factors, such as epidermal growth factor or insulin-like growth factor-1, which in turn regulate bone development and maintenance.^[15][13] Accordingly, male and female ERKO mice exhibit decreased bone length and size.^[15][13]

Brain

In patients with breast cancer, mutations in the gene encoding ERα (ESR1) have been associated with resistance to endocrine therapy, especially aromatase inhibitors.^[26]

Coactivators

Coactivators of ER-α include:

• SRC-1^[27][28]
• AIB1 – amplified in breast 1^[29]
• BCAS3 – Breast carcinoma amplified sequence 3^[30]
• PELP-1 – Proline-, glutamic acid-, leucine-rich protein 1^[31]

Interactions

Estrogen receptor alpha has been shown to

References