Abstract
BackgroundPsychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk.MethodsWe investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1.ResultsWe found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression.ConclusionsHyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.
Highlights
Psychiatric medications are widely prescribed in the USA
This subset of mammary epithelial cells was made susceptible to replication-competent avian sarcoma (RCAS) infection by transgenic expression of the gene encoding the RCAS receptor TVA from the MMTV promoter (MMTV-tva) [34]
We explored the effect of several antipsychotics on mammary cancer development from preexisting early lesions
Summary
Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. Mammary cell differentiation caused by PRL-PRLR-JAK2-STAT5 signaling is a mechanism by which an early-age pregnancy reduces breast cancer risk [11]. We have reported that STAT5 activation in preexistent precancerous lesions in mice instigates accelerated progression to cancer via suppression of the apoptosis anticancer barrier [11] This finding provides an explanation for increased breast cancer risk associated with a late-age pregnancy when early lesions may have already formed. Activated forms of JAK2 and STAT5 have been reported in human early breast lesions and cancer [7, 12,13,14,15,16] and in other human cancers [7, 17]
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