PROLACTIN AND CISPLATIN COMBINATION TREATMENT INHIBITS TUMORSPHERE FORMATION AND DELAYS BREAST TUMOR GROWTH IN MICE

Cancer stem cells (CSC) are defined as a small population of cells in tumor that areresponsible for the tumor initiation,resistance and recurrence.Chemo-resistance remainsto be one of the major obstacles in conventional chemotherapies. One of the reasons that majority of chemotherapeutics are not effective in eradicating cancer cellsis due to the existence of CSC, which are usually in a non-proliferative or dormant state.In this paper, we hypothesized that in order to improve the outcome of conventional chemotherapy,it will be more effective to utilizeCSC stimulating factorsin combination with conventional chemotherapeutics. The current studyaimed to investigate the feasibility of using prolactin (PRL), a hormone intimately involved in mammary gland development,in combination with cisplatinas an alternative to target breast CSC (BCSC). Using tumorsphere formation assaywe demonstrated that PRL was able to alter the cancer cell proliferation pattern in tumorspheres, which accompanied with increased CD44+24- cell population. We further showed that PRL treatment reducedthe ability of breast cancer cells to form tumorspheres.Moreover, PRL significantly enhanced cisplatin's inhibitory effects intumorsphere formation. The IC50 value of cisplatin was reduced by more than half with the addition of PRL in tumorsphere formation assay.The efficacy of this combinational approach wasfurther confirmed through in vivo experiments (McNeuallograft tumor growth and 4T1 total survival rate). Finally,PRL and cisplatin combination treatment significantly delayednaturally developed breast tumor growth in neutransgenic mice. Taken together, ourstudy provided evidence to support the hypothesis that the addition of PRLto conventional chemotherapy (cisplatin) may be an effectivealternative to target BCSC.