Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions

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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0969-z) contains supplementary material, which is available to authorized users.

Ganoderma Lucidum Polysaccharide, an Extract from Ganoderma Lucidum, Exerts Suppressive Effect on Cervical Cancer Cell Malignancy through Mitigating Epithelial-Mesenchymal and JAK/STAT5 Signaling Pathway

“…Data from Giordano et al [30] illustrated that the changes of the JAK/STAT5 signaling pathways in colorectal cancer can improve the therapeutic effects mediated by LY6G6D. Recent work by Johnston et al [31] has established that psychotropic drugs can increase the risk of breast cancer by activating the JAK/STAT5 signaling pathways in precancerous lesions. Moreover, studies of Lopez et al [32] showed the importance of JAK/STAT5 in cervical cancer cells.…”

T-Type Calcium Channels: A Potential Novel Target in Melanoma

“…However, Mibefradil has been recently reapproved, under the condition of "orphan medication," so that its efficacy for the treatment of pancreatic cancer, glioblastoma multiforme, and ovarian cancer can be investigated (clinicaltrials.gov). Similarly, Pimozide-an antipsychotic drug-is also a strong inhibitor of TTCCs that inhibits tumor cell proliferation and decreases cell migration in hepatocellular carcinoma [51], prostate cancer [52], breast cancer [53], and melanoma [54]. Consequently, the inhibition of TTCCs affects their functionality; therefore, the cellular functions involved are compromised.…”

Mortality of site-specific cancer in patients with schizophrenia: A systematic review and meta-analysis

“…Evidence supports the possible increased risk of breast cancer in women with schizophrenia due partly to the use of antipsychotic medications [29], some of which may cause hyperprolactinaemia, which, in turn, may contribute to mammary development and breast carcinogenesis in animal and cell experiments [30,31]. Johnston et al found that two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, incite precancerous cells to progress to cancer by activating JAK-STAT5 signaling [32]. Patients with schizophrenia show decreased incidence of prostate cancer [25,33], which is theoretically related to low testosterone levels suppressed by high prolactin levels on account of antipsychotic drug use [34].…”