Estrogen Receptor-α Variant, ER-α36, is Involved in Tamoxifen Resistance and Estrogen Hypersensitivity

Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to TAM therapy. The molecular mechanisms underlying TAM resistance have not been well established. Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-alpha 36, a variant of ER-alpha, benefited less from TAM therapy than those with low concentrations of ER-alpha 36, suggesting that increased ER-alpha 36 concentration is one of the underlying mechanisms of TAM resistance. Here, we investigated the function and underlying mechanism of ER-alpha 36 inTAM resistance. We found that TAM increased ER-alpha 36 concentrations, and TAM-resistant MCF7 cells expressed high concentrations of ER-alpha 36. In addition, MCF7 cells with forced expression of recombinant ER-alpha 36 and H3396 cells expressing high concentrations of endogenous ER-alpha 36 were resistant to TAM. ER-alpha 36 down-regulation in TAM-resistant cells with the short hairpinRNA method restored TAM sensitivity. We also found that TAM acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-alpha 36-expressing cells. Finally, we found that cells with high concentration of ER-alpha 36 protein were hypersensitive to estrogen, activating ERK phosphorylation at picomolar range. Our results thus demonstrated that elevated ER-alpha 36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape TAM therapy and provided a rational to develop novel therapeutic approaches for TAM-resistant patients by targeting ER-alpha 36.