Abstract P6-02-01: Apoptotic cell clearance lies at the interface of post-lactational involution and breast cancer

Background. Cytokines that promote wound healing and immune tolerance are profoundly upregulated during post-lactational involution of the breast and promote tumor growth and malignancy. This observation is supported by increasing evidence that post-lactational involution produces a highly malignant microenvironment contributing to poor outcome of pregnancy associated breast cancers (PABCs) which arise within 5 years of a full-term pregnancy. We have discovered that one mechanism driving cytokine modulation during post-lactational involution is efferocytosis, or the phagocytic clearance of apoptotic cells (ACs). Cell death is a prominent feature of the post-lactational breast, when up to 90% of the entire epithelial content dies and must be removed, making this an ideal model to study both apoptosis and AC clearance. Without efferocytosis, residual ACs undergo secondary necrosis, which stimulates acute inflammation and expression of Th1 cytokines. Thus, efferocytosis prevents secondary necrosis of dying cells, enhances immune tolerance and wound healing through production of Th2 cytokines. In healthy post-lactational breast tissue this is an optimal physiological response that promotes breast remodeling. However, in the context of breast cancer, efferocytosis may be pro-tumorigenic. Results. We have shown that post-lactational efferocytosis is necessary to re-establish breast tissue homeostasis after lactation, and for re-initiating successful lactation after future pregnancies. We have also demonstrated that during the earliest phases of post-lactational involution, the breast epithelium is the primary phagocytic resource in the breast, although it is clear that macrophages engulf dying cells during later stages of involution. We have identified the receptor tyrosine kinase MerTK as a necessary mediator of efferocytosis and subsequent cytokine modulation during post-lactational involution. Further, MerTK-mediated cytokine changes in the post-lactational mammary microenvironment promotes malignant progression of spontaneously forming PABC in a transgenic mouse model, as genetic targeting of MerTK decreased tumor growth and metastasis without altering tumor latency. Post-lactational tumors expressed abundant Th2 and wound healing cytokines as compared to tumors in nulliparous mice. However, loss of MerTK in post-lactational mammary tumors impaired the expression of Th2 and wound healing cytokines, while inducing the expression of Th1 cytokines. Conclusion. These results suggest that efferocytosis-mediated cytokine regulation is a key driver of malignant severity in pregnancy associated mammary tumors. These data are consistent with our previous demonstrations that MerTK in the mammary tumor microenvironment increases tumor malignancy. Targeted inhibition of MerTK may decrease efferocytosis-mediated cytokine modulation in breast tumors to limit pro-tumorigenic cytokine production and stimulate production of cytokines associated with anti-tumor immunity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-01.