Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.
Background: Psychiatric 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 ap...
| Publicado en: | Breast Cancer Research Vol. 20; no. 1 |
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| Autores principales: | , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
5/19/2018
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=129694097&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 129694097 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 5/19/2018 vid: 20 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 129694097 129694097 NLM29778097 129694097 10.1186/s13058-018-0969-z NLM29778097 129694097 ppct: 1 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions. aug: au: Johnston, A. N. Bu, W. Hein, S. Garcia, S. Camacho, L. Xue, L. Qin, L. Nagi, C. Hilsenbeck, S. G. Kapali, J. Podsypanina, K. Nangia, J. Li, Y. affil: Translational Biology and Molecular Medicine, Baylor College of Medicine 77030 Houston TX USA sug: subj: Precancerous Conditions Breast Neoplasms Carrier Proteins Proteins Female Breast Pathology Heterocyclic Compounds Adverse Effects Risperidone Adverse Effects Signal Transduction Drug Effects Hyperpituitarism Chemically Induced Breast Neoplasms Epidemiology Mice Human Breast Neoplasms Pathology Breast Neoplasms Chemically Induced Apoptosis Drug Effects Risk Factors Antipsychotic Agents Adverse Effects Precancerous Conditions Chemically Induced Hyperpituitarism Epidemiology Precancerous Conditions Pathology Hyperpituitarism Pathology Breast Drug Effects Hyperpituitarism Animal Studies Cell Differentiation Drug Effects Validation Studies Comparative Studies Evaluation Research Multicenter Studies Impact of Events Scale Scales Female ab: Background: Psychiatric 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.Methods: We 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.Results: We 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.Conclusions: Hyperprolactinemia-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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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