Interactions between BRD4S, LOXL2, and MED1 drive cell cycle transcription in triple-negative breast cancer

Triple-negative breast cancer (TNBC) often develops resistance to single-agent treatment, which can be circumvented using targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 synergistically limits TNBC proliferation in vitro and in vivo. Mechanistically, LOXL2 interacts in the nucleus with the short isoform of BRD4 (BRD4S), MED1, and the cell cycle transcriptional regulator B-MyB. These interactions sustain the formation of BRD4 and MED1 nuclear transcriptional foci and control cell cycle progression at the gene expression level. The pharmacological co-inhibition of LOXL2 and BRD4 reduces BRD4 nuclear foci, BRD4-MED1 colocalization, and the transcription of cell cycle genes, thus suppressing TNBC cell proliferation. Targeting the interaction between BRD4S and LOXL2 could be a starting point for the development of new anticancer strategies for the treatment of TNBC. imageInvestigation of the molecular mechanisms underlying triple-negative breast cancer (TNBC) proliferation led to the identification of new therapeutic vulnerabilities.LOXL2 expression predicted cancer cells response to BET inhibitor (BETi).LOXL2 interacted with the short isoform of BRD4 (BRD4S) and MED1 in the nucleus of TNBC cells.LOXL2-BRD4S-MED1 interactions were responsible for regulating cell cycle gene expression.Combined inhibition of LOXL2 and BRD4 disrupted LOXL2-BRD4S-MED1 interaction, MED1-BRD4 colocalization, and the formation of BRD4 transcriptional foci.Combined inhibition of LOXL2 and BRD4 suppressed TNBC proliferation in vitro and in vivo. Investigation of the molecular mechanisms underlying triple-negative breast cancer (TNBC) proliferation led to the identification of new therapeutic vulnerabilities.image

Automated summary

The simultaneous inhibition of LOXL2 and BRD4 has been found to effectively suppress the proliferation of triple-negative breast cancer (TNBC), offering a potential new strategy for its treatment. By disrupting the interactions between LOXL2 and BRD4, the transcriptional regulation of cell cycle genes is affected, leading to the suppression of TNBC cell proliferation.