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

Breast Cancer Research : BCR
A N JohnstonY Li

Abstract

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. 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. 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. H...Continue Reading

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Citations

Nov 7, 2019·Cancers·Kelsey L PolakMark W Jackson
Jul 4, 2019·The EMBO Journal·Pirashaanthy TharmapalanRama Khokha
Feb 13, 2020·Cancers·Carla BarcelóAnna Macià
Dec 22, 2020·Journal of Clinical Psychopharmacology·Tahir RahmanEric J Lenze
Apr 2, 2021·Journal of Pharmaceutical Health Care and Sciences·Tae MaeshimaFumio Itagaki
Oct 29, 2020·Seminars in Cell & Developmental Biology·Ödül Karayazi AtıcıCarrie S Shemanko
Jun 3, 2021·Cancers·Dana C BorcherdingNira Ben-Jonathan
Nov 30, 2021·Journal of Biomolecular Structure & Dynamics·Nurcan GumusBurcin Tezcanli Kaymaz
Oct 21, 2021·Cancer Prevention Research·Adelaide YoungYi Li

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Methods Mentioned

BETA
transgenic
ELISA

Software Mentioned

ImageJ
R
R commander

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