Breast cancer subtypes display distinct biological traits that influence
their clinical behavior and response to therapy. Recent studies have
highlighted the importance of chromatin structure regulators in
tumorigenesis. The RNF20-RNF40 E3 ubiquitin ligase complex
monoubiquitylates histone H2B to generate H2Bub1, while the
deubiquitinase (DUB) USP44 can remove this modification. We found that
RNF20 and RNF40 expression and global H2Bub1 are relatively low, and
USP44 expression is relatively high, in basal-like breast tumors
compared with luminal tumors. Consistent with a tumor-suppressive role,
silencing of RNF20 in basal-like breast cancer cells increased their
proliferation and migration, and their tumorigenicity and metastatic
capacity, partly through upregulation of inflammatory cytokines. In
contrast, in luminal breast cancer cells, RNF20 silencing reduced
proliferation, migration and tumorigenic and metastatic capacity, and
compromised estrogen receptor transcriptional activity, indicating a
tumor-promoting role. Notably, the effects of USP44 silencing on
proliferation and migration in both cancer subtypes were opposite to
those of RNF20 silencing. Hence, RNF20 and H2Bub1 have contrasting roles
in distinct breast cancer subtypes, through differential regulation of
key transcriptional programs underpinning the distinctive traits of each
subtype