ProMyelocytic Leukemia protein IV (PMLIV) represses breast cancer proliferation by modulating the FOXO3-FOXM1 axis
Ontology highlight
ABSTRACT: The multitasking ProMyelocytic Leukemia (PML) protein, which was originally recognized as tumor suppressive factor, is commonly lost in primary breast cancer tissue samples. However, PML’s role in breast cancer is still debated, as high PML levels reportedly correlate with cancer cell pro-survival activity and poor patient prognosis in a subset of breast cancer types. To study the molecular mechanisms underlying the involvement of PML in cell proliferation and self-renewal pathways in breast cancer, a transgene expressing PMLIV upon doxycycline treatment was stably integrated in MDA-MB-231 cells (tetPMLIV MDA-MB-231 cells), a claudin-low, triple negative, aggressive breast cancer cell line. Here, we report that inducible PMLIV expression leads to reduced proliferation rates and self-renewal of breast cancer cells as well as to impaired cell cycle progression. To further dissect PML’s role in breast cancer growth, we performed genome-wide expression analysis on MDA-MB-231 PMLIV overexpressing (OE) and control cells cultured in monolayer as well as in sphere conditions. Transcriptomic profiling identified many deregulated genes and their cognitive transcription factors. Upon PMLIV induction the Forkhead box subclass M1 (FOXM1) factor is itself suppressed at both the RNA and protein level, and consequently many of its cell cycle target genes. We show that FOXM1 interacts with PMLIV primarily via its DNA binding domain and that dynamically co-localizes in PML nuclear bodies. In parallel, PMLIV enhances the activity of FOXO3, a factor opposing some of the FOXM1 outputs, to promote cell survival and stress resistance. We propose that PMLIV may favour both anti-proliferative and pro-survival pathways at variable levels, dictated by genetic or epigenetic cancer cell states that may account for its disparate effects in cancer.
ORGANISM(S): Homo sapiens
PROVIDER: GSE119583 | GEO | 2019/06/16
REPOSITORIES: GEO
ACCESS DATA