Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

ERβ is a member of the family of estrogen receptors and the superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17-β-estradiol, estriol or related ligands, the encoded protein forms homo-dimers or hetero-dimers with estrogen receptor α that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized.

ERβ may inhibit cell proliferation and opposes the actions of ERα in reproductive tissue. ERβ may also have an important role in adaptive function of the lung during pregnancy.

ERβ is a potent tumor suppressor and plays a crucial role in many cancer types such as prostate cancer and ovarian cancer.

ERβ knockout mice show normal mammary gland development at puberty and are able to lactate normally. The mammary glands of adult virgin female mice are indistinguishable from those of age-matched wild-type virgin female mice. This is in contrast to ERα knockout mice, in which a complete absence of mammary gland development at puberty and thereafter is observed. Administration of the selective ERβ agonist ERB-041 to immature ovariectomized female rats produced no observable effects in the mammary glands, further indicating that the ERβ is non-mammotrophic.

Although ERβ is not required for pubertal development of the mammary glands, it may be involved in terminal differentiation in pregnancy, and may also be necessary to maintain the organization and differentiation of mammary epithelium in adulthood. In old female ERβ knockout mice, severe cystic mammary disease that is similar in appearance to postmenopausal mastopathy develops, whereas this does not occur in aged wild-type female mice. However, ERβ knockout mice are not only deficient in ERβ signaling in the mammary glands, but also have deficient progesterone exposure due to impairment of corpora lutea formation. This complicates attribution of the preceding findings to mammary ERβ signaling.

Selective ERβ agonism with diarylpropionitrile (DPN) has been found to counteract the proliferative effects in the mammary glands of selective ERα agonism with propylpyrazoletriol (PPT) in ovariectomized postmenopausal female rats. Similarly, overexpression of ERβ via lentiviral infection in mature virgin female rats decreases mammary proliferation. ERα signaling has proliferative effects in both normal breast and breast cancer cell lines, whereas ERβ has generally antiproliferative effects in such cell lines. However, ERβ has been found to have proliferative effects in some breast cell lines.

Expression of ERα and ERβ in the mammary gland have been found to vary throughout the menstrual cycle and in an ovariectomized state in female rats. Whereas mammary ERα in rhesus macaques is downregulated in response to increased estradiol levels, expression of ERβ in the mammary glands is not. Expression of ERα and ERβ in the mammary glands also differs throughout life in female mice. Mammary ERα expression is higher and mammary ERβ expression lower in younger female mice, while mammary ERα expression is lower and mammary ERβ expression higher in older female mice as well as in parous female mice. Mammary proliferation and estrogen sensitivity is higher in young female mice than in old or parous female mice, particularly during pubertal mammary gland development.