The Role of ERα36 in Development and Tumor Malignancy

Estrogen nuclear receptors, represented by the canonical forms ER alpha 66 and ER beta 1, are the main mediators of the estrogen-dependent pathophysiology in mammals. However, numerous isoforms have been identified, stimulating unconventional estrogen response pathways leading to complex cellular and tissue responses. The estrogen receptor variant, ER alpha 36, was cloned in 2005 and is mainly described in the literature to be involved in the progression of mammary tumors and in the acquired resistance to anti-estrogen drugs, such as tamoxifen. In this review, we will first specify the place that ER alpha 36 currently occupies within the diversity of nuclear and membrane estrogen receptors. We will then report recent data on the impact of ER alpha 36 expression and/or activity in normal breast and testicular cells, but also in different types of tumors including mammary tumors, highlighting why ER alpha 36 can now be considered as a marker of malignancy. Finally, we will explain how studying the regulation of ER alpha 36 expression could provide new clues to counteract resistance to cancer treatments in hormone-sensitive tumors.