Three decades on from the first reports of numerous isoforms and splice variants of estrogen receptor alpha (ERα) and later of estrogen receptor beta (ERβ), both receptors still present a very open issue. It is not pretentious to say that there is a “mystery” regarding their biological role and clinical significance, especially in endocrine related cancers. While ERα is a well-established prognostic marker for responsiveness to endocrine therapy in breast cancer, a significant number of ERα-positive patients fail to respond to therapy or develop resistance over time. Moreover, the role of ERα and ERβ is implicated in other types of cancer (ovarian, colorectal, prostate, endometrial, and sarcomas), as well as in osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity.

The intriguing question today is whether the ERα and ERβ, their isoforms, and internal-exon-deleted splice variants are potential disease markers, especially in the triple negative breast cancer subgroup for which adequate treatment regimens are not available. Moreover, the role of ERβ as disease marker is often implicated in nonendocrine cancers and different nonmalignant pathologies.

What can we learn about them from earlier studies with competitive RT-PCR, compared to qRT-PCR till chip-based methodology? Do all of the splice variants exist at protein level? How do they influence the activity of full length (wild type) proteins ERα and ERβ? Are they potential disease markers?

The aim of this issue is to summarize the state of the art in biological function and clinical potential of the ERs “pool” in normal and malignant cells. Research articles as well as reviews are welcome.

Potential topics include but are not limited to the following:

• The emergent need for precise nomenclature of different N-terminal isoforms of ERα and C-terminal isoforms of ERβ, as well as for internal-exon-deleted splice variants
• Experimental evidence that internal-exon-deleted splice variants are translated into proteins
• Expression profiling of isoforms and variants in cancers and other pathologies
• Biological role of isoforms and the splice variants of ERα and ERβ
• The clinical importance of isoforms and splice variants of the ERα and ERβ in terms of prediction, prognosis, and therapeutical potential