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Estrogen alpha and beta subtype analysis in breast carcinomas - Newer prognostic marker in the making?

 Department of Pathology, K S Hegde Medical Academy of Nitte University, Mangalore, Karnataka, India

Date of Submission10-May-2020
Date of Decision03-Jun-2020
Date of Acceptance10-Jul-2020

Correspondence Address:
HL Kishan Prasad,
Department of Pathology, K S Hegde Medical Academy, Mangalore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_244_20

How to cite this URL:
Kishan Prasad H L. Estrogen alpha and beta subtype analysis in breast carcinomas - Newer prognostic marker in the making?. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 May 10]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=309334

The estrogen hormone is responsible for various physiological processes such as cell growth, development, and differentiation.[1],[2],[3],[4],[5] The estrogen receptor (ER) signaling abnormality leads to a variety of diseases such as cancers, metabolic/cardiovascular disease, neurodegenerative diseases, inflammation, and osteoporosis.[2],[3],[4] The ER-alpha (ER-α) and beta (ER-β) are the transcription factors which are involved in the regulation of various physiological processes in human beings. ER-α is usually expressed in reproductive organs such as uterus and ovary and other organs such as breast, kidney, bone, adipose tissue, and liver. The ER-β is generally expressed in ovary, brain, heart, lung, male reproductive organs, prostate, colon, kidney, and the immune system. These ER receptors have some typical physiological roles, such as the development and function of the ovaries and in the protection of the cardiovascular system. The ER-α subtype is responsible for the growth of mammary gland and uterus, with the preservation of skeletal homeostasis and metabolic regulation. The ER-β type has a counteractive function with ER-α promoted hyperproliferation of cells in breast and uterine tissues. Based on the above concepts, the modulation of these receptors by targeted therapeutic agents is currently being considered for treatment and prevention of a wide variety of pathological conditions, such as cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis.[1],[2],[3],[4],[5]

The carcinoma of the breast is the most frequently diagnosed nonskin cancer among women worldwide. It has a 5-year survival rate of 63% in the early 1960s to 89% currently in developed countries. The adjuvant hormone therapy in breast carcinomas has helped achieve this substantial reduction in mortality since 75% of breast cancers express ERs.[4],[5] The estrogens play a central role in the development and growth of both normal and malignant mammary tissues. They mediate most of their action through the ER-α; hence, this receptor status analysis in breast tumors provides prognostic information and is the primary target for endocrine therapy. The ER-α is expressed in <10% of normal breast epithelium (both in ductal and lobular epithelial and stromal cells), but approximately 50%–80% of breast tumors. The treatment strategies to treat ER-positive breast tumors include the agents that compete with the binding to its receptors, such as selective ER modulators like tamoxifen, raloxifene and toremifene and antiestrogens or reducing the levels of circulating estrogens by the third-generation aromatase inhibitors such as anastrozole, letrozole, and exemestane. These have shown to be more effective than tamoxifen in postmenopausal women in neoadjuvant and adjuvant settings.[3],[4],[5]

Tamoxifen is effective and widely used antiestrogen therapy for breast cancer. However, only 70% of ER-α-positive breast cancers respond to tamoxifen treatment and 30%–40% of patients receiving therapy.[4],[5]

In breast carcinomas, ER-α is responsible for the increased proliferation, whereas this is counteracted by the presence of ER-β, which exerts an antiproliferative effect. The breast cancer patients with estrogen responsive disease should respond positively to treatment with ER–α antagonists and/or ER-β agonists. It was shown that the ductal carcinomas in the initial stage show the high expression of ER α and low expression of ER β. The high-grade invasive ductal cancers then lose the expression of both of these receptors. The early-stage lobular breast cancer showed abundant levels of both ER α and ER β, whereas advanced stages of these type of carcinomas present only ER α expression with ER β negativity. Hence, the use of ER β-selective agonists only in the case of early-stage ductal cancer, since it may prevent or delay the development of the more invasive disease. However, an ER-α antagonist may be helpful for the treatment of advanced lobular cancer (but not early-stage disease), or early-stage ER-α positive ductal cancer.[3],[4],[5] Despite the initial positive responses to tamoxifen therapy, one-third of all patients will develop resistance, though their ER-α status may remain unchanged. A lower expression of ER-β is found in tamoxifen-resistant tumors, and high levels of ER-β are occasionally associated with a better clinical outcome in ER-α positive breast tumors. Several studies have suggested that the expression of ER-β independently predicts better disease-free survival in patients treated with tamoxifen. However, some data have suggested that the positivity of ER-β is associated with low cellular differentiation, which indicates that this receptor could be related to worse overall survival. Hence, the assessment of ER-β together with ER-α is a better predictor of endocrine responsiveness than ER-α alone. Few studies have suggested that ER-β correlates with Progesterone Receptor (Pg R) and expression together with ER-α, it is possible that ER-α and ER-β could be better biomarkers than ER-α and Pg R. It is also possible that analysis of these three receptors in combination will provide the most precise prediction of endocrine responsiveness.[4],[5]

Few of the studies comparing neoadjuvant and adjuvant endocrine treatments are now available. However, the expression of ER-α has been extensively studied as a predictive marker of treatment response, the role of ER-β remains controversial and has never been examined in a neoadjuvant short-term trial.[3],[4],[5]

Hence, it is time for a researcher to come with ER-α and ER-β expression among various breast carcinomas, its relation with grading and staging of the disease. It is an area of research to lay the firm foundation of diverse biological roles of ER-α or ER-β in different tissues and further studies will help in the development of receptor specific targeted therapies for the management of various pathological disorders.

  References Top

Paterni I, Granchi C, Katzenellenbogen JA, Minutolo F. Estrogen receptors alpha (ERa) and Beta (ERβ): Subtype-selective ligands and clinical potential. Steroids 2014;90:13-29.  Back to cited text no. 1
Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res 2012;28:71-6.  Back to cited text no. 2
Clipperton AE, Spinato JM, Chernets C, Pfaff DW, Choleris E. Differential effects of estrogen receptor alpha and beta specific agonists on social learning of food preferences in female mice. Neuropsychopharmacology 2008;33:2362-75.  Back to cited text no. 3
Jia M, Wright KD, Gustafsson AK. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab 2015;29:557-68.  Back to cited text no. 4
Madeira M, Mattar A, Logullo AF, Soares FA, Gebrim LH. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer 2013;13:425.  Back to cited text no. 5


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