Promyelocytic Leukemia (PML) gene regulation: implication towards curbing oncogenesis

Dysregulation of PML, a significant tumor suppressor is linked with cancers of different histological origins, with a decreased expression observed with a higher tumor grade. This necessitates studying the mechanisms to maintain a stable expression of PML. However much less is known about the transcriptional regulation of PML, more so in the context of breast carcinoma. ER beta has emerged as a critical factor in understanding breast cancer, especially since a huge proportion of breast cancers are ER alpha(-) and thus insensitive to tamoxifen therapy. This study aims to uncover an unidentified mechanism of PML gene regulation and its stabilization in breast cancer via ER beta signalling and the impact on cellular apoptosis. We found that clinical expression of PML positively correlates with that of ER beta both in normal and breast carcinoma samples and inversely correlates with markers of cellular proliferation, hinting towards a possible mechanistic interdependence. Both mRNA and protein expression of PML were increased in response to ER beta overexpression on multiple human breast cancer cell lines. Mechanistically, luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that ER beta can interact with the PML promoter via ERE and AP1 sites to enhance its transcription. ER beta induced stable PML expression causes a decline of its target protein Survivin and simultaneously provides a stable docking platform leading to stabilisation of its target Foxo3a, further causing transcriptional upregulation of pro-apoptotic factors p21 and p27. Immunohistochemical analyses of cancer and normal breast tissues and functional assays conducted corroborated the findings. Collectively, our study identifies ER beta signalling as a novel mechanism for PML gene regulation in ER alpha(-) breast cancer. It also reveals bi-directional downstream effect in which 'ER beta-PML-(Foxo3a/Survivin)' network acts as a therapeutic axis by suppressing cellular survival and promoting cellular apoptosis in breast carcinoma.