Describe the main findings from your paper.
We demonstrate that the coordinated activation of c-Src and FOXM1 in breast cancer leads to cell-cycle deregulation, accelerated proliferation, and tumor progression. Additionally, loss of c-Src鈥搈ediated phosphorylation of FOXM1 or pharmacological targeting of FOXM1 blocks the cell cycle by suppressing the expression of G2/M-phase genes and of c-Src itself. This disrupts the positive feedback loop and impairing tumor progression and metastasis of aggressive luminal breast cancers.
What do you think makes this paper stand out from other papers in the field?
This paper stands out from other papers in the field as this is the first study to describe the closely coordinated expression of c-Src and FOXM1 in human breast cancers. We show that c-Src-dependent tyrosine phosphorylation of FOXM1 promotes its nuclear localization and activates the expression of cell-cycle progression genes as well as c-Src itself. This positive feedback loop drives proliferation and interfering with the regulatory network centered on c-Src and FOXM1 may improve patient outcome. This is especially important, as clinical trials of Src inhibitors in solid tumors yield mixed or poor results. As such, specific targeting essential functions downstream of c-Src, such as FOXM1, is integral in developing effective therapeutic strategies for cancer patients.
What was your favourite experiment in this paper, and how was it conducted?
My favourite experiment in this paper was culturing 3D organotypic cultures and subjecting these organoids to immunofluorescence and transcriptomic analysis. Organoids have revolutionized cancer biology and therapeutics as it has enabled scientists to test new therapies before they are approved for clinical trials. These experiments allowed us to visualize the effects on proliferation, apoptosis and localization of specific proteins with genetic and pharmacological inhibition of c-Src and FOXM1.
How do you think your lab, or other researchers, could expand on this work?
The current standard of care for metastatic hormone receptor-positive (Estrogen Receptor a and Progesterone Receptor) breast cancers are endocrine therapies and more recently inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/-6). However, these compounds are limited by the development of therapeutic resistance and may be less effective against Luminal B tumors compared with Luminal A as they express lower levels of ERa, exhibit a higher proliferative rate and more aggressive metastatic behavior. Preliminary findings suggest that breast cancer cells that are resistant to these inhibitors are dependent FOXM1, establishing a potential indication for the clinical translation of small molecule inhibitors of FOXM1.
In what ways did working on this project help you grow as a scientist?
As this was my first manuscript as the primary author, this experience showed me how to organize my data into a cohesive story and how to critically analyze which pieces of data were missing and would be crucial to support our hypothesis and findings. Additionally, this project has demonstrated the importance of developing international collaborations with experts in the field in order to conduct better science and improve patient care.
Congratulations to Ipshita and to all researchers involved in this project for their hard work and for this exciting publication!听