Prolactin and DNA Damage Trigger an Anti-Breast Cancer Cell Immune Response

Ödül Karayazi AticiNayantara GovindrajanIsbel Lopetegui GonzálezConstance FinneyCarrie S Shemanko^*

• University of Calgary, Calgary, Canada

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. Here, we investigated the role of PRL in tumour initiation and the effect of DNA damage. We used an in vivo model to assess the ability of breast cancer cells to initiate orthotopic xenograft tumour formation after DNA damage. Breast cancer cells engineered to secrete human PRL were treated with the DNA damaging agent doxorubicin and injected into the mammary fat pad of immune-deficient severe combined immunodeficiency disease (SCID) mice. Doxorubicin and PRL combination increased tumour latency, although PRL secretion alone did not change the tumour latency compared to controls. 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. Additionally, doxorubicin plus PRL treatment of breast cancer cells was shown in vitro to attract cytotoxic NK cells compared to controls, and this was dependent on the PRLR. These results demonstrate that combined breast cancer cell DNA damage and PRL exposure results in anti-tumour cell activity of asialo-GM1-positive immune cells.