Oncogene. 2017 Sep 18. doi: 10.1038/onc.2017.311. [Epub ahead of print]
EZH2 contributes to the response to PARP inhibitors through its PARP-mediated poly-ADP ribosylation in breast cancer.
Yamaguchi H1, Du Y1, Nakai K1, Ding M2, Chang SS1, Hsu JL1, Yao J1, Wei Y1, Nie L1, Jiao S1, Chang WC3,4, Chen CH3, Yu Y2, Hortobagyi GN5, Hung MC1,4,6.
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Abstract
Inhibitors against poly (ADP-ribose) polymerase (PARP) are promising targeted agents currently used to treat BRCA-mutant ovarian cancer and are in clinical trials for other cancer types, including BRCA-mutant breast cancer. To enhance the clinical response to PARP inhibitors (PARPis), understanding the mechanisms underlying PARPi sensitivity is urgently needed. Here, we show enhancer of zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation and associates with oncogenic function, contributes to PARPi sensitivity in breast cancer cells. Mechanistically, upon oxidative stress or alkylating DNA damage, PARP1 interacts with and attaches poly-ADP-ribose (PAR) chains to EZH2. PARylation of EZH2 by PARP1 then induces PRC2 complex dissociation and EZH2 downregulation, which in turn reduces EZH2-mediated H3 trimethylation. In contrast, inhibition of PARP by PARPi attenuates alkylating DNA damage-induced EZH2 downregulation, thereby promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARPi-untreated cells. Moreover, the addition of an EZH2 inhibitor sensitizes the BRCA-mutant breast cells to PARPi. Thus, these results may provide a rationale for combining PARP and EZH2 inhibition as a therapeutic strategy for BRCA-mutated breast and ovarian cancers.Oncogene advance online publication, 18 September 2017; doi:10.1038/onc.2017.311.
Hi Semir, I am grateful for this insight. She has a branch mutation in BRCA2 that evolved on Liquid biopsy not in the previous tumor, so this is quite interesting.... Also there is an interesting paper that astemizole the FDA approved anti histamine works to inhibit EZH2...
Best regards,
M~
Interesting. We (Drs Palazzo, Gatalica and I) recently published a study on metaplastic breast carcinoma. BRCA2 mutations were uncommon, but may be occasionally seen.
What about PD-L1 in this case? It is commonly overexpressed in metaplastic carcinoma. Please see our paper on metaplastic carcinoma profiling:
Article Comprehensive profiling of metaplastic breast carcinomas rev...
She is PD-L1 positive - we got it off CTC's in bone marrow...! Think Caris would loike to license that? - The company is about to go out of business....
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