Abstract
Estrogen receptor α (ERα or ER) is the only target of breast cancer therapy using antiestrogens. However, about 50% of ER-expressing breast cancer is intrinsically refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed. Dynamic ER phosphorylation and dephosphorylation play an important role in ER activity and antihormone response. Although more than 10 kinases participate in phosphorylating ER protein, phosphatases involved remain mostly unidentified. Here, we tested the hypothesis that the protein-tyrosine phosphatase H1 (PTPH1) may regulate ER tyrosine phosphorylation and thereby impact breast cancer antihormone sensitivity. Our results showed that PTPH1 dephosphorylates ER at Tyr537 in vitro and in breast cancer cells. Moreover, PTPH1 stimulates ER nuclear accumulation and increases breast cancer sensitivity to tamoxifen (TAM) and/or fulvestrant in cell culture and in a xenograft model. Further analysis revealed that PTPH1 depends on its catalytic activity to stimulate ER nuclear accumulation and to enhance breast cancer antihormone sensitivity. These studies thus identified PTPH1 as a novel ER phosphatase and further demonstrate a therapeutic potential of enhancing breast cancer sensitivity to antiestrogens through dephosphorylating ER by PTPH1.
Highlights
Estrogen receptor a (ERa or ER) is expressed in about 70% of breast cancer and is activated by estrogen and growth factors to regulate expression of genes important for breast cancer growth [1]
Our results presented here have advanced this field by demonstrating that ER dephosphorylation at a critical residue such as Y537 is important for breast cancer response to antihormone therapy through increasing ER nuclear accumulation
We showed that protein-tyrosine phosphatase H1 (PTPH1) dephosphorylates ER/Y537 in vitro and in breast cancer cells acting as a novel ER phosphatase (Fig. 1)
Summary
Estrogen receptor a (ERa or ER) is expressed in about 70% of breast cancer and is activated by estrogen and growth factors to regulate expression of genes important for breast cancer growth [1]. ER serves as a key target for antihormone therapy by using antiestrogens such as tamoxifen (TAM) and fulvestrant [2]. About 50% of ER–positive (ERþ) breast cancers are refractory to the antihormone therapy and strategies to improve the therapeutic response are urgently needed [2, 3]. ER is an important nuclear receptor and phosphorylation plays an important role in determining ER activity and hormone response by a residue-specific mechanism [2, 4]. In response to estrogen and growth factors, for example, ER is phosphorylated at S118 by ERK Increased levels of Authors' Affiliations: 1Department of Pharmacology and Toxicology, Medical College of Wisconsin; 2Research Services, Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin; and 3Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
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