Estrogen receptor alpha-36 (ER-α36): A new player in human breast cancer

• ER-α36 is a novel variant of ER-α that is expressed in breast cancer.
• ER-α36 is primarily localized in the cytoplasm and at the plasma membrane.
• ER-α36 mediates rapid estrogen signaling.
• ER-α36 is involved in antiestrogen resistance of human breast cancer.
• ER-α36 is a novel player in breast cancer stem/progenitor cells.

Prevailing wisdom is that estrogen receptor (ER)-α mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-α, ER-α36, and found that ER-α36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-α36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-α36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross-talk of ER-α36 with other ERs and growth factor receptors, and intracellular pathways of ER-α36-mediated rapid estrogen signaling. The potential function and underlying mechanism of ER-α in development of ER-positive breast cancer will also be discussed.