The significance of oestrogen and progesterone receptors in breast cancerCorrespondence Address :
Dr. Varghese C.,Mumbai INDIA
It was 40 years ago, that the importance of steroid hormone receptors in the biology of breast cancer was recognized. This important finding was the result of a study in which radiolabelled oestrogens concentrated preferentially in the oestrogen-influenced target organs of animals, and also in human breast cancers. Thus, the concept of an oestrogen receptor (ER) was established. Ever since, it has been observed that human breast cancers are dependent upon oestrogen and/or progesterone for growth, and that this effect is mediated through ERs and progesterone receptors (PRs). Thus ER and PR are both found to be overexpressed in malignant breast tissue. Oestrogen receptor (ER) and/or progesterone receptor (PR) expressing breast cancers are found to have different clinical, pathological, and molecular features. They have been found to play a significant role in the prognosis and treatment of breast cancers. Recent developments which provided new insights into hormone receptor biology and the increasing array of proteins that can modify their function, have helped modulate better therapies for breast cancer.(eg). ,Selective oestrogen receptor modulators (SERMS), which are drugs that interact with the oestrogen receptor, have been approved for the treatment and prevention of breast cancer. Also, less expensive, simpler, and possibly more accurate measurements of ER and PR have been made possible by methods for assaying receptor proteins.
oestrogen receptor, progesterone receptor, prognosis, breast cancer, tamoxifen, aromatase inhibitors
Female reproductive activity is mainly regulated by oestrogen and progesterone receptors. Oestrogen and progesterone regulate the normal development of the ovary, the uterus and the mammary gland through their cognate receptors, and play key roles in the tumorigenesis of these tissues. It has been observed that oestrogen controls the early ductal morphogenesis of the mammary gland, whereas progesterone controls ductal branching and alveolar development of the mammary gland during pregnancy, as has been demonstrated by studies on the oestrogen receptor (ER) and PR knockout mice(1).
In spite of considerable homology between these receptor forms, it is their structural and functional differences that may be important for tissue and promoter- specific regulation of gene expression.
Breast cancers classified by oestrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathological, and molecular features. Exposure to oestrogen during reproduction carries a high risk of ER-positive tumour formation, than ER-negative tumour formation. Nulliparous women and those who had delayed childbearing, carry a high risk to develop ER positive tumours than ER-negative tumours. ER/PR positive tumours were found to be associated with early menarche than ER-negative/PR-negative tumours. The possibility of increased oestrogen synthesis in adipose stores and greater bioavailability, has been reflected in hormone receptor positive tumours. It is probably due to this reason, that postmenopausal obesity has been found to be more consistently associated with increased risk of hormone receptor-positive, than hormone receptor-negative tumours(2). Oestrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive) breast cancer patients are found to have lower risks of mortality after their diagnosis, compared to women with ER- and/or PR-negative disease (3). A lower rate of cell proliferation and histological evidence of tumour differentiation has been found to be favourable prognostic features in patients with positive receptor status. ER and PR have their greatest significance in predicting response to hormonal therapy, both in the adjuvant setting, and for advanced disease(4),(Table/Fig 1)
About the receptors
Both ER and PR belong to the nuclear hormone receptor superfamily, that includes the androgen and retinoid receptors. Being located in the cytosol of target cells, they operate as ligand-dependent transcription factors. The DNA-binding sites on the receptor are unmasked by the attachment of a lipid-soluble hormone to the ligand-binding domain . This causes the receptors to migrate into the nucleus, and bind to specific hormone responsive elements near the genes that are responsible for the physiologic actions of the hormone. This is followed by transcription of messenger RNA and ribosomal RNA, and the eventual synthesis of new proteins(5).
It has been observed that only about 50 to 70 percent of breast cancers require the female hormone oestrogen (oestradiol) to grow; other breast cancers are able to grow without oestrogen. Molecules called hormone receptors, which are essential for the cell to use oestrogen for growth, are produced by oestrogen-dependent breast cancer cells. These hormone receptors can be either oestrogen or progesterone receptors, or both. The development and growth of breast cancers are promoted by oestrogens and genetic changes together. ER is present in more than half of breast tumours, because oestrogenic hormones act via the oestrogen receptors (ERs), ER-alpha and ER-beta, and thus, this receptor has been the most widely targeted protein in breast cancer therapy. Women are significantly more likely to benefit
Treatment of cancer patients can be revolutionized by the identification and exploitation of biomarkers that may predict response to anti-cancer treatments. In breast cancer, the oestrogen receptor (ER) and the progesterone receptor (PR) are known to have a significant predictive value in determining sensitivity to endocrine therapies. Clinical outcome is affected by tumour expression of ER or PR, and this information is often used to determine a patient's optimal treatment regimen. However, the measurement of ER and PR alone is more complex than originally thought, and due to the recently identified isoforms of ER (ERα and ERβ) and PR (PRA and PRB), as well as several variant and mutant forms, the choice of treatment remains difficult. The recent advances in genomic- or proteomic-based approaches has enabled to understand the molecular picture of breast cancers , which in turn, allows biomarkers of response and prognosis to be identified and characterized more accurately than before. In the future, to maximize the therapeutic benefit of the patients, they could be treated according to the molecular portrait of their tumour biomarker expression(22).
Oestrogen and progesterone receptors are known prognostic indicators in breast cancer. The response of breast cancer to a particular therapy can be determined by its oestrogen receptor positivity status. Breast cancer drugs like tamoxifen and aromatase inhibitors act by suppression of oestrogen receptor activity.
Conflict of Interest: None Declared
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