Targeting PML in triple negative breast cancer elicits growth suppression and senescence

Abstract

Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.

Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis

“…Co-transfection of cMYC with Firefly-luciferase reporter system fused to TRIB1 promoter in HEK293T cells resulted in significant increase in luciferase luminescence ( Figure 2 D, Figure S4C ). On the other hand, cMYC silencing with a previously validated doxycycline-inducible shRNA system [ 36 , 57 ] resulted in a significant decrease in TRIB1 mRNA abundance in PC3 cells ( Figure 2 E). A similar effect was found in the breast cancer cell line MDAMB231 (a cell line which does not exhibit copy number alterations in TRIB1 according to the Cell Line Encyclopedia [ 58 ]), thus suggesting that this might be a general mechanism of regulation ( Figure S4D ).…”

The Role of ND10 Nuclear Bodies in Herpesvirus Infection: A Frenemy for the Virus?

“…Although the complete or partial loss of functional PML is a hallmark for various tumors [ 63 , 65 ], higher expression of PML has also been reported in tumors such as ovarian carcinoma and triple-negative breast cancer (TNBC) [ 23 , 73 ]. Interestingly, recent results showed that PML knockdown in cultured cells derived from these tumors induced apoptosis in the ovarian carcinoma cells and senescence response in the TNBC cells and thereby inhibited the cell proliferation in tissue culture or mouse xenograft [ 23 , 73 ], suggesting the pro-tumor roles of PML and ND10 in these particular cancers.…”

“…Although the complete or partial loss of functional PML is a hallmark for various tumors [ 63 , 65 ], higher expression of PML has also been reported in tumors such as ovarian carcinoma and triple-negative breast cancer (TNBC) [ 23 , 73 ]. Interestingly, recent results showed that PML knockdown in cultured cells derived from these tumors induced apoptosis in the ovarian carcinoma cells and senescence response in the TNBC cells and thereby inhibited the cell proliferation in tissue culture or mouse xenograft [ 23 , 73 ], suggesting the pro-tumor roles of PML and ND10 in these particular cancers. Further investigation in the TNBC cells demonstrated that arsenic treatment, which triggers PML degradation [ 74 ], did not elicit the senescence response like that of PML knockdown [ 23 ], indicating that distinctive methods of removing PML can lead to differential cellular response, something analogous to what has been shown in the HSV-1 studies, which are discussed in the next section.…”

“…Interestingly, recent results showed that PML knockdown in cultured cells derived from these tumors induced apoptosis in the ovarian carcinoma cells and senescence response in the TNBC cells and thereby inhibited the cell proliferation in tissue culture or mouse xenograft [ 23 , 73 ], suggesting the pro-tumor roles of PML and ND10 in these particular cancers. Further investigation in the TNBC cells demonstrated that arsenic treatment, which triggers PML degradation [ 74 ], did not elicit the senescence response like that of PML knockdown [ 23 ], indicating that distinctive methods of removing PML can lead to differential cellular response, something analogous to what has been shown in the HSV-1 studies, which are discussed in the next section. More complex pro-cancer functions of PML have been found in the maintenance of leukemia stem cells, neuroblast migration, and TNBC metastasis [ 75 , 76 , 77 ].…”

“…The diversity and importance of ND10 proteins in a cell’s life have kept these nuclear bodies in the scientific spotlight for decades, yet how ND10 bodies dynamically shift the components to orchestrate a specific function is still not well understood. Recent studies on both the virology and cancer biology fronts have implied that ND10 may play dual roles and serve as a frenemy in establishing the viral replication and tumor malignancy [ 22 , 23 ], which have attracted further interest in the complex functions of ND10.…”