Estrogen drives cellular proliferation and survival in estrogen receptor-positive (ER+) breast cancer. Exposure to endogenous or exogenous estrogen is a well-established cause of breast cancer and target of endocrine therapies such as antiestrogens and aromatase inhibitors. However, their efficacy is limited by intrinsic or acquired endocrine resistance which remains a significant clinical challenge. A third of patients given the antiestrogen therapy tamoxifen for 5 years develop recurrence and metastasis within 15 years. Gene expression studies of endocrine resistance suggest the dysregulation of epigenetic enzymes has an important role in survival signaling and cellular proliferation in acquired endocrine resistance. The development of epigenetic modifier inhibitors offers the promise of dynamically targeting mediators of acquired resistance that may be exploited as biomarkers and therapeutic targets to improve patient prognosis.
The in vitro work was performed using endocrine-resistant and endocrine-sensitive breast cancer cell lines. Proliferation was measured by changes in cellular confluency over time and viability determined by MTT assay. In vivo studies were investigated using a mouse xenograft model.
In this study, we identified a histone methyltransferase that is regulated epigenetically and when targeted in combination with endocrine therapy it significantly reduces the proliferation and the viability of resistant cells in vitro, and it leads to a significant reduction in tumour growth in a mouse xenograft model.
Tamoxifen and histone methyltransferase inhibitor reduce proliferation and viability of tamoxifen-resistant and sensitive breast cancer cell lines. Histone methyltransferase inhibitor re-sensitises resistant breast cancer and causes tumour regression in a mouse xenograft model. Therefore, tamoxifen-resistant ER+ breast cancer can be re-sensitised by epigenetic therapy.
QIMR Berghofer
QIMR Berghofer
All authors have declared no conflicts of interest.