Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Breast Cancer Res. 2018 May 19;20(1):42. doi: 10.1186/s13058-018-0969-z.
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.
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.
精神科药物在美国被广泛应用。许多抗精神病药物会导致血清催乳素升高，这是一种不良的副作用；催乳素-Janus 激酶 2（JAK2）-信号转导子和转录激活子 5（STAT5）信号均能诱导细胞分化并抑制细胞凋亡。这些抗精神病药物是否会增加乳腺癌风险尚存争议。
我们研究了几种抗精神病药物对逆转录病毒介导的 ErbB2 或 HRas 传递或 Wnt-1 转基因表达引发的乳腺肿瘤发生的影响。
我们发现，两种引起高催乳素血症的抗精神病药利培酮和匹莫齐特促使癌前病变进展为癌症，而不会引起高催乳素血症的阿立哌唑则不会。我们观察到，利培酮和匹莫齐特（但不是阿立哌唑）导致癌前细胞激活 STAT5 并抑制细胞凋亡，而对增殖没有影响。重要的是，我们证明了抗精神病药对早期病变的这些作用需要 STAT5 基因功能。此外，我们表明，仅用 JAK1/2 抑制剂鲁索利替尼治疗小鼠两周即可阻断 STAT5 激活、恢复细胞凋亡并阻止早期病变进展。
高催乳素血症诱导的抗精神病药通过 JAK/STAT5 诱导癌前细胞进展为癌症，从而抑制了抗癌凋亡屏障，而这种促癌作用可以通过预防性抗 JAK/STAT5 治疗来预防。这项临床前研究揭示了某些患者中高催乳素血症诱导的抗精神病药可能存在乳腺癌风险，并提出了一种化学预防方案，与已经或可能已经发展为癌前病变的女性标准 5 年抗雌激素治疗相比，这种方案相对容易实施，同时也需要使用高催乳素血症诱导的抗精神病药。
