Emergence of β1 integrin-deficient breast tumours from dormancy involves both inactivation of p53 and generation of a permissive tumour microenvironment

The molecular and cellular mechanisms underlying mammary tumour dormancy and cancer recurrence are unclear and remain to be elucidated. Here, we report that mammary epithelial-specific disruption of beta 1 integrin in a murine model of Luminal B human breast cancer drastically impairs tumour growth with proliferation block, apoptosis induction and cellular senescence. beta 1 integrin-deficient dormant lesions show activation of the tumour suppressor p53, and tumours that circumvent dormancy possess p53 mutation analogous to those in human disease. We further demonstrate that mammary epithelial deletion of p53 in beta 1 integrin-deficient mice fully rescues tumour dormancy and bypasses cellular senescence. Additionally, recurrent beta 1 integrin-deficient tumours exhibit fibrosis with increased cancer-associated fibroblast infiltration and extracellular matrix deposition, absent in fast-growing beta 1 integrin/p53-deficient lesions. Taken together, these observations argue that beta 1 integrin modulates p53-dependent cellular senescence resulting in tumour dormancy and that pro-tumourigenic stromal cues and intrinsic genetic mutation are required for dormancy exit.

Automated summary

The study demonstrates that β1 integrin plays a crucial role in the growth and dormancy of mammary tumors, affecting tumor dormancy through p53-dependent cellular senescence. Dormant tumors show activation of p53, and mutations in p53 similar to those in human disease are found in tumors that bypass dormancy.