Systemic Mobilization of Breast Cancer Resistance Protein in Response to Oncogenic Stress

SIMPLE SUMMARY: The drug efflux mediated by xenobiotic transporters is one of the best recognized mechanisms of multidrug resistance in cancer that leads to the failure of therapeutic approaches. The aim of our research was to examine the influence of a growing tumor on the activity of xenobiotic transport in the host. Our study reveals a strong correlation between the development of melanoma tumor in mice and the level of breast cancer resistance protein, one of the major xenobiotic transporters, and its transcript in the normal tissues of the hosts distant from the tumor site. The systemic effects of the tumor are confirmed by a drastically enhanced xenobiotic transport, which is correlated with changes in the level of cytokines in blood. Such an unexpected type of tumor–host interaction, which leads to the systemic upregulation of breast cancer resistance protein, and very likely of other xenobiotic transporters too, has broad implications for cancer therapies, including chemotherapy and photodynamic therapy. Our findings shed new light on the biology of cancer and the complexity of cancer–host interactions that should be taken into account in the design of new generations of anti-cancer drugs and personalized medicine. ABSTRACT: The breast cancer resistance protein (BCRP or ABCG2) involved in cancer multidrug resistance (MDR), transports many hydrophobic compounds, including a number of anti-cancer drugs. Our comprehensive study using a mouse model reveals that a subcutaneously growing tumor strongly affects the expression of BCRP in the host’s normal organs on both the transcriptional and translational level. Additionally, the efflux of BCRP substrates is markedly enhanced. The levels of BCRP and its transcript in normal tissues distant from the tumor site correlate with tumor growth and the levels of cytokines in the peripheral blood. Thus, oncogenic stress causes transient systemic upregulation of BCRP in the host’s normal tissues and organs, which is possibly mediated via cytokines. Because BCRP upregulation takes place in many organs as early as the initial stages of tumor development, it reveals a most basic mechanism that may be responsible for the induction of primary MDR. We hypothesize that such effects are not tumor-specific responses, but rather constitute a more universal defense strategy. The xenobiotic transporters are systemically mobilized due to various stresses, seemingly in a pre-emptive manner so that the body can be quickly and efficiently detoxified. Our findings shed new light on the biology of cancer and on the complexity of cancer–host interactions and are highly relevant to cancer therapies as well as to the design of new generations of therapeutics and personalized medicine.