Signalling Network of Breast Cancer Cells in Response to Progesterone

Abstract

Breast cancer cells enter into the cell cycle following progestin exposure by the activation of signalling cascades involving a plethora of enzymes, transcription factors and co-factors that transmit the external signal from the cell membrane to chromatin, ultimately leading to a change of the gene expression program. Although many of the events within the signalling network have been described in isolation, how they globally team up to generate the final cell response is unclear. In this study we use antibody microarrays and phosphoproteomics to provide a dynamic global signalling map that reveals new key regulated proteins and links between previously known and novel pathways. Detailed analysis of the data revealed intriguing changes in protein complexes involved in nuclear structure, EMT, cell adhesion, as well as transcription factors previously not associated with breast cancer proliferation. As different post-translational modifications can mediate complex crosstalk mechanisms and massive PARylation is also rapidly induced by progestins, we provide details of important chromatin regulatory complexes containing both phosphorylated and PARylated proteins. This study contributes an important resource for the scientific community, as it identifies novel players and connections meaningful for breast cancer cell biology and potentially relevant for cancer management.

Role of the NUDT Enzymes in Breast Cancer

“…To address this, we carried out a global phosphoproteomic analysis over time from antibody arrays and mass spec datasets in order to determine the signaling pathways induced by progesterone in breast cancer cells. As expected, we identified the rapid activation of the MAPK cascade, but we were also able to reconstruct activation of new kinase signaling networks previously not associated with breast cancer cell response to progesterone, including ERBB-EGF, Fc receptor, insulin, and TRK (Tropomyosin receptor kinase) signaling cascades [ 64 ]. In addition, we identified signaling networks involved in the processes of EMT, cell adhesion, and angiogenesis, which is consistent with our hypothesis and previous work and with the role of NUDT5 in aggressive cancer progression ( Figure 2 [ 25 ]).…”

“…We have recently contributed to the understanding of breast cancer progression via the analysis of phosphoproteomic datasets [ 64 ]. As discussed earlier, NUDT5 generates ATP in the nucleus of breast cancer cells in response to progesterone, dependent on degradation of PARP1 synthesize PAR to ADPR by PARG.…”