PRL and DNA damage alter the immune response to breast cancer cells

Abstract

There are conflicting reports on the role of prolactin (PRL) in breast cancer, and its role within the context of the tumour microenvironment is not well understood. In our previous study, we demonstrated a cross-talk between the ataxia telangiectasia-mutated (ATM) DNA damage response pathway and the PRL-Janus-kinase-2 (JAK2)-signal transducer and activator of transcription-5 (STAT5)-heat shock protein-90 (HSP90) pathway. To investigate the role of PRL in tumour initiation and the effect of DNA damage in vivo, we used a model of breast cancer initiation that assesses the ability of breast cancer cells to initiate orthotopic xenograft tumour formation after DNA damage. Breast cancer cells engineered to secrete human PRL or the control cells, were treated with the DNA damaging agent doxorubicin or vehicle and injected into the mammary fat pad of immune-deficient SCID mice. PRL secretion from human breast cancer cells did not change the tumour latency compared to controls, although combined doxorubicin and PRL treatment increased tumour latency. Depletion of glycolipid asialo ganglioside-GM1 positive immune cells using anti-asialo GM1 antibody resulted in faster tumour formation only in the PRL-secreting breast cancer cells that were pre-treated with doxorubicin, and not in the PRL-only or empty vector controls. Additionally, doxorubicin plus PRL treatment of breast cancer cells were shown in vitro to attract cytotoxic NK cells compared to controls, and that this was dependent on the PRLR. These results may shed light on the conflicting reports of PRL in breast cancer and demonstrate that combined breast cancer cell DNA damage and PRL exposure results in anti-tumour activity of asialo-GM1-positive immune cells.