Inhibition of UCHL1 enhances the sensitivity of estrogen receptor negative breast cancer cells to endocrine therapy

抄録

Breast cancer is the most common malignant tumors among women in the worldwide. The status of estrogen receptor in breast cancer is usually associated with prognosis and response to hormonal therapy. estrogen receptor status varies among breast cancers, with one third of the disease showing estrogen receptor negative. Absence of estrogen receptor is known to be associated with poor differentiation of tumor cells, resistance to hormonal therapy, and poor clinical outcome; thus, a better understanding of the causes and mechanisms underlying the loss or reduction of estrogen receptor in breast cancer may help identify novel strategy for treating breast cancer. We recently found that the expression of ubiquitin C terminal hydrolaseL1 (UCHL1), an enzyme that uniquely possesses both ubiquitin hydrolase and ligase activity, is conversely related with estrogen receptor status in breast cancer. UCHL1 is overexpressed in estrogen receptor (-) breast cancer cell lines and tumor samples, but is barely detectable in estrogen receptor (+) breast cancer cell lines and tumor samples. Overexpression of UCHL1 in estrogen receptor (+) cells resulted in a remarkable reduction of estrogen receptor mRNA and protein; however, UCHL1 inhibitor or UCHL1 siRNA upregulated the protein and mRNA levels of estrogen receptor in estrogen receptor (-) cells. We further demonstrated that the regulatory effect of UCHL1 on estrogen receptor resulted from this deubiquitylase-mediated stability of EGFR, which promotes the transcription of estrogen receptor. Inhibition of UCHL1 could significantly enhance the sensitivity of estrogen receptor (-) breast cancer cells to tamoxifen, the most commonly used anti estrogen agent in the treatment of this disease. These data demonstrated that UCHL1 may be a potential molecule target to sensitize hormone resistant human breast cancers to anti estrogen agent. Our findings not only provided a basis for new approaches to upregulating estrogen receptor level, but also present a new rationale strategy for developing more effective therapies for estrogen receptor negative breast cancer, and a new pharmacologic target for drug development.