Metrics details. 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
Coly, P. Besides cell proliferation, evasion of apoptosis serves a key role in the Foursome playboy screencaps of precancerous early lesions to cancer [ 5455 ]. All these lines of evidence underscore the potential of repurposing sertindole as an antitumor agent for clinical treatment. References 1. When tumors reached 2. Similarly, treatment of a delirious or agitated patient may require the relatively safer short-term use of an antipsychotic. Powered By Decision Support Psychiatric drugs inducing breast cancer Medicine. After gathering Ms. We recorded whether patients were exposed to any dopamine antagonists, individual agents, and pharmacologic classes, including phenothiazines acetophenazine, chlorpromazine, fluphenazine, mesoridazine, perphenazine, promazine, thioridazine, and trifluoperazinethioxanthenes chlorprothixene and thiothixeneand butyrophenones haloperidol.
Nylon sexy. Change Password
Access to Experimental Drugs. Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy and there is no evidence of risk in later trimesters. Questions to Ask about Advanced Cancer. An increased risk for these drugs would suggest an association confounded by psychiatric comorbidity and Psychiatric drugs inducing breast cancer risk factors, assuming that elevated prolactin is the sole biological mechanism by which exposure affects breast cancer risk. Show me more Exposure to different antipsychotics was standardized using olanzapine equivalents Deciding to Take Part in a Trial. YL is the principal Supermodel pic dickerson for this project. Baker, M. Previous Figure Next Figure. FDA alerts. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis. Hanahan D, Weinberg RA.
Thank you for visiting nature.
- People with serious mental illness — schizophrenia , bipolar disorder and disabling depression — are 2.
- E-mail address: apottegaard health.
- Metrics details.
Enter your email address below and we will send you the reset instructions. If the address matches an existing account you will receive an email with instructions to reset your password.
If the address matches an existing account you will receive an email with instructions to retrieve your username. Search for more papers by this author. Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group.
These drugs are well known to elevate serum prolactin levels to varying degrees. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer. Antipsychotic drugs approved for clinical use by the U. Food and Drug Administration FDA are packaged with precautions regarding their administration to patients with established breast cancer.
Because of the potential for antipsychotics to cause complications in patients with breast cancer, careful consideration is required before prescribing these agents for women with breast cancer who have a comorbid mental illness. While no clear causal link has been established between the use of antipsychotics and the risk of breast cancer, many antipsychotics are known to elevate serum prolactin levels, and a significant body of evidence supports a role for prolactin in both the pathobiology and the progression of established breast cancer 1 — 3.
Compared with normal mammary cells, cancerous breast cells overexpress the prolactin receptor PRLr. Prolactin supports the proliferation, survival, motility, invasion, and anchorage-independent growth an acquired ability to grow without attachment to a basement membrane of both estrogen receptor ER -positive and ER-negative breast cancer cells 4 — 7. We present a review of pertinent studies of tumorigenesis carried out at the cellular level involving both human and mouse models and discuss the evidence that antipsychotic agents may adversely affect women with established breast cancer.
Recommendations and a rationale for treating such patients are also discussed. Prolactin is a neuroendocrine hormone that is normally elevated during pregnancy and lactation. Prolactin not only is secreted by the pituitary gland, but also is produced in a variety of tissues, such as breast, lymphocytes, uterus, prostate, and placental decidua. Medical conditions such as pituitary tumor, stress, hypothalamic disorders, liver disease, and kidney disease can also elevate prolactin levels.
It is well established that prolactin levels become elevated as a response to many antipsychotic drugs, with resulting side effects that may include amenorrhea, galactorrhea, osteoporosis, and loss of libido. The secretion of prolactin by the anterior pituitary involves many feedback loops.
Hypothalamic inhibition of lactotroph cells, which normally release prolactin, occurs via a dopamine-mediated portal pathway known as the tuberoinfundibular tract. Antipsychotic drugs block dopamine D 2 receptors within this tract, resulting in increased serum prolactin levels.
Since the available data are correlative, the question of whether or not elevated prolactin levels actually cause breast cancer is open to discussion. In addition, breast cancer patients with elevated prolactin levels have more rapid disease progression and a lower survival rate 10 , Whether prolactin plays a role in new breast cancer development in patients with a genetic or other predisposition to the disease remains to be determined. Another study 13 suggested that an elevated risk of breast and other cancers after the first diagnosis of schizophrenia could be attributed to nongenetic factors, such as treatment with antipsychotics.
Thus, to date, no clear association between chronic administration of antipsychotics and mammary tumorigenesis has been demonstrated in clinical studies. Her symptoms were well controlled, with no apparent side effects. A was seen every 4—6 months for medication refills, and she usually had no complaints. Although she presented as an anxious individual, she was generally high functioning and had a successful business career and a happy marriage. She was intelligent, highly organized, and detail-oriented.
Her health had always been excellent; she exercised several times a week, had never smoked cigarettes, had no history of substance abuse, and ate a healthy diet. Eighteen months earlier, Ms. A had found a lump on her right breast during self-examination and was subsequently diagnosed with breast cancer.
She underwent a single mastectomy for a 2-cm lesion. Endocrine therapy with tamoxifen was recommended for a total of 5 years.
During the months following her chemotherapy, Ms. A visited her primary care physician regularly in a distressed state, upset and crying, and she complained of insomnia and loss of appetite. Her primary care physician prescribed alprazolam, 0. A gradually accepted her cancer condition.
She attended support groups and consulted a therapist. She is now being seen with her husband as a new patient in our clinic because she wanted another opinion regarding her medications.
With the new diagnosis of breast cancer and additional health care expenses, she became concerned that the insurance copayment for aripiprazole plus the additional cancer expenses would be unaffordable. She also learned of the hormonal effects of antipsychotic drugs by reading the drug package inserts, and she now seeks information about the safety of the antipsychotic medication she was receiving.
After gathering Ms. A ran the risk of elevated prolactin levels. Her depression was found to be similar to her previous depressive episodes and not just demoralization from a cancer diagnosis. Therefore, other treatment options were discussed, including increasing the dosage of sertraline, augmenting with another type of medication, replacing sertraline with another antidepressant, adding psychotherapy, and trying ECT.
This was a lower-cost regimen and helped reassure the patient. She also responded well to cognitive therapy, education about her treatment, and the development of an alternative treatment plan should her condition worsen.
After several months, the clonazepam was successfully tapered off. Prolactin action is mediated by the PRLr, which is a member of the cytokine receptor superfamily Loss of the PRLr in breast cancer cells results in a dramatic reduction in ER and progesterone receptors PR , revealing another mechanism through which the PRLr may regulate breast cancer growth i. Many genes that are activated by PRLr in breast cancer cells are associated with tumorigenesis and cell proliferation Activation of these kinases induces the phosphorylation and activation of latent transcription factors such as Stat3 and Stat5 18 , The PRLr and other receptors, such as epidermal growth factor receptor EGFr , ER, and integrin receptors, are known to play a role in breast cancer Recent evidence also indicates that the PRLr has a direct nuclear function as a transcriptional coactivator that coordinates the actions of Stat5 and the nucleosome-binding protein HMGN2 on the prolactin-driven Stat5-responsive promoter chromatin 16 , Prolactin promotes mammary cancer in rodent models.
Warning labels accompanying FDA-approved antipsychotic drugs caution physicians that chronic administration of these drugs has been associated with an increase in mammary neoplasms in rodents. This warning is based on findings predominantly from models in which the effects of prolactin are determined in mammary cells that are genetically similar to human breast cancer cells.
Two types of transgenic models are used to study the effects of prolactin in mice. Prolactin transgenic mice develop a mix of ER-positive and ER-negative mammary tumors that are histologically similar to human breast tumors 22 , When prolactin transgenic mice are crossed with established models of murine mammary tumorigenesis, tumor development is accelerated The potential of antipsychotic drugs to cause prolactin elevation has been well documented in the literature and is included on all product labeling.
Although recent controlled investigations are somewhat lacking for first-generation antipsychotics, several studies have reported twofold to tenfold increases in plasma prolactin levels in some patients.
The effects of second-generation antipsychotics have been much better documented over the past two decades, given their recent approvals and their established role as first-line treatment agents. The elevations in serum prolactin levels associated with each agent can be compared from different studies to give us an estimation of the possible risks accompanying their use.
Table 1 , compiled from available data on FDA-approved antipsychotic drugs 26 — 33 , presents the relative effects of commonly prescribed antipsychotics on prolactin levels.
Data drawn from references 26 — In general, first-generation antipsychotics cause significant elevations in serum prolactin levels. Of the second-generation drugs, risperidone and its separately marketed active metabolite, paliperidone, raise prolactin levels the most. This is because these two drugs cross the blood-brain barrier poorly, and as a result, serum concentrations of risperidone and paliperidone must be higher than those of other antipsychotics in order to achieve CNS levels sufficient to exert their therapeutic effects.
The pituitary is located outside the blood-brain barrier, and therefore the effect of these drugs on D 2 receptors is greater 30 , A number of second-generation antipsychotics appear to have minimal effects on serum prolactin levels. Aripiprazole may even lower prolactin levels because of its partial agonist effect on the dopamine receptor 28 , Therefore, in the case of Ms. A, switching from aripiprazole to risperidone would not be deemed advisable. Clinicians routinely administer antipsychotic drugs to patients suffering from both a mental illness and breast cancer.
However, many clinicians and their patients may be unaware of the potentially harmful effects that may be associated with the use of such drugs in this patient population. The widespread acceptance and clinical use of antipsychotics to treat a diverse array of mental conditions—bipolar disorder, major depression, autism spectrum disorders, tic disorders, dementia, and schizophrenia, as well as various off-label uses—may pose an unforeseen risk in patients with established breast cancer.
In the absence of controlled studies, it is difficult to predict how a particular antipsychotic might affect the prognosis for a woman with breast cancer. In fact, the role of serum prolactin levels is not currently an established predictor in the management of breast cancer. However, blocking the prolactin receptor has been identified as an important area of potential treatment for breast cancer Considering the precautions that accompany antipsychotic drugs, and given the current available research data, a prospective study to determine the potentially harmful effects of such drugs would be considered unethical by most standards.
Hence, we have combined relevant preclinical research data, FDA precautions, and some epidemiological evidence from the fields of cellular pathology, pharmacology, oncology, and psychiatry to help inform the practicing physician about the possibility of harmful side effects accompanying the use of antipsychotics in patients with breast cancer. As with any case, clinicians must weigh the potential benefits and risks of treatment and nontreatment.
It is advisable that the oncologist, psychiatrist, and other relevant clinicians be involved together with the patient or possibly the family and guardian to arrive at an informed decision. The duration of antipsychotic treatment, the severity and type of mental illness, potential effects on serum prolactin levels, ethical considerations, and breast cancer staging may all require careful consideration.
Since prolactin appears to promote breast cancer development irrespective of receptor status, breast cancer receptor typing is not a factor when it comes to making the decision of whether or not to prescribe an antipsychotic.
All women with intraductal breast cancers should be assumed to have an elevated risk of prolactin-related progression of the disease if they are treated with antipsychotic medication.
Additionally, other risks of these drugs, such as metabolic side effects, may play a yet unknown role in breast cancer survival rates. For example, insulin resistance, genetics, parity, diet, smoking, dyslipidemia, abdominal obesity, and hypertension are all associated with a higher incidence of breast cancer 35 , Increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cancer cell proliferation and survival.
Clozapine and olanzapine have been reported to decrease levels of adiponectin The effect, if any, of these parameters on breast cancer risk or recurrence requires further investigation. Patients with severe psychotic illnesses such as schizophrenia are often treated with depot formulations to enhance treatment adherence.
The risk of seriously exacerbating a psychotic condition by avoiding or discontinuing antipsychotic treatment may outweigh the risk of elevating levels of prolactin by administering an antipsychotic.
Understanding Cancer. LQ performed the initial experiments in this study. The effect of neuroleptics on serum prolactin in schizophrenic patients. Daily news summary. Questions to Ask about Advanced Cancer. Other anxiety disorders.
Psychiatric drugs inducing breast cancer. Related Services
As these are not only risk factors for breast cancer, but might also be associated with use of antipsychotics either positively or inversely , uncontrolled confounding from these factors might bias our findings. However, the results of the probabilistic bias analysis showed that these were unlikely to account for the observed association, conditional on the accuracy of the bias model.
This lack of substantial bias is a function of the relatively low prevalence of these confounders and the relatively low strength of association between these risk factors and breast cancer risk, both of which diminish the potential for these factors to confound the association. While dose—response patterns were generally weak, they did suggest a dose—response effect, especially for risperidone and olanzapine. Such a dose—response pattern is less likely to be explained by unmeasured confounding than is the overall result.
All the same, it is worth noting that our reported association is of approximately the same magnitude as some other established—but much more prevalent—breast cancer risk factors. Analysis stratified by oestrogen receptor status showed that the observed associations were specific to oestrogen receptor positive breast cancers. This finding in accordance with results from studies on prolactin levels and risk of breast cancer 16 , The possible underlying mechanisms are not well substantiated.
It has been demonstrated that activation of nuclear prolactin receptor induces the expression of oestrogen receptors in breast cancer cells 46 , The only other study 26 that specifically addressed the use of FGA nested their analysis within antipsychotic ever users and found no increased risk when comparing SGA to FGA, which is in line with our findings of a comparable risk between the two.
Further, they found no evidence of a dose—response pattern. Other studies hold no or indiscriminate information on exposure to SGA. Wang et al. From the paper, it is not possible to identify cases exposed specifically to risperidone. Last, a case—control study of women diagnosed with primary invasive breast cancer within the preceding year found no association with prior phenothiazine use exposed The increased risk specifically for cancers, classified as unclassified carcinoma , was a surprising finding for which we have no plausible explanation.
One could consider whether diagnostic workup might be different in the face of severe psychiatric disorders. However, as we only included histologically verified cancers, this would require that the pathological evaluation differed according to psychiatric comorbidity, which is unlikely.
In conclusion, our results, from what is the most extensive set of data reported to date, do not suggest an overall clinically important association between exposure to SGA — or any antipsychotic drugs — and risk of breast cancer. Martin T. Ernst University of Southern Denmark is acknowledged for valuable help with data management.
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries other than missing content should be directed to the corresponding author for the article. Volume 84 , Issue 9. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.
If the address matches an existing account you will receive an email with instructions to retrieve your username. Society Member login bps. British Journal of Clinical Pharmacology. Timothy L. Thomas P. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access.
Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Abstract Aims Some antipsychotics increase prolactin levels, which might increase the risk of breast cancer. Results In total, cases 8. Conclusions Overall, our results do not suggest a clinically important association between antipsychotic use and risk of breast cancer. Introduction Breast cancer is one of the most commonly diagnosed malignant diseases worldwide 1.
Main exposure variables and covariates Exposure to different antipsychotics was standardized using olanzapine equivalents Main analysis The analysis followed a conventional matched case—control approach. Sensitivity and supplementary analyses We performed several preplanned subanalyses and sensitivity analyses. Other All analyses were performed using Stata Release Figure 1 Open in figure viewer PowerPoint.
Ever use 1. Competing Interests There are no competing interests to declare. Breast cancer. Crossref Google Scholar. Crossref PubMed Google Scholar. Google Scholar. Citing Literature. Volume 84 , Issue 9 September Pages Figures References Related Information.
Close Figure Viewer. Browse All Figures Return to Figure. Previous Figure Next Figure. Email or Customer ID. Forgot password? Old Password. New Password. Password Changed Successfully Your password has been changed. Returning user. Request Username Can't sign in? Forgot your username? Enter your email address below and we will send you your username. Lobular adenocarcinoma. Adenocarcinoma, not otherwise specified. Carcinoma, not otherwise specified. Never use any antipsychotic.
Late Effects of Childhood Cancer Treatment. Pediatric Supportive Care. Unusual Cancers of Childhood Treatment. Childhood Cancer Genomics. Study Findings. Metastatic Cancer Research. Intramural Research. Extramural Research. Bioinformatics, Big Data, and Cancer. Frederick National Laboratory for Cancer Research. Spotlight on Scientists. Cancer Biology Research.
Cancer Genomics Research. Research on Causes of Cancer. Cancer Diagnosis Research. Cancer Prevention Research. Cancer Treatment Research. Cancer Health Disparities. Childhood Cancers Research. Clinical Trials Research. Global Cancer Research. Annual Report to the Nation. Milestones in Cancer Research and Discovery. Stories of Discovery. Terminology Resources.
Research Grants. Research Funding Opportunities. Research Program Contacts. Funding Strategy. Grants Policies and Process. Introduction to Grants Process.
NCI Grant Policies. Legal Requirements. Step 3: Peer Review and Funding Outcomes. Manage Your Award. Grants Management Contacts.
Prior Approvals. Annual Reporting and Auditing. Transfer of a Grant. Grant Closeout. Cancer Training at NCI. Resources for Trainees. Funding for Cancer Training. Building a Diverse Workforce. Resources for News Media. Media Contacts. Cancer Reporting Fellowships. Advisory Board Meetings.
Social Media Events. Cancer Currents Blog. Contributing to Cancer Research. Strategic Planning. Previous NCI Directors. Advisory Boards and Review Groups. NCI Congressional Justification. Current Congress. Committees of Interest. Legislative Resources. Recent Public Laws. Search Search. Cancer Treatment. Radiation Therapy. External Beam Radiation. Side Effects. Checkpoint Inhibitors. T-cell Transfer Therapy.
Metrics details. 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 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. 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.
Psychiatric medications are among the top five drugs in sales in the USA [ 1 ]. Both typical class 1 and atypical class 2 antipsychotics also known as neuroleptics act by antagonizing dopamine and thus blocking post-synaptic dopamine D2 receptors in the pituitary gland; atypical antipsychotics additionally suppress serotonin receptors [ 2 ].
Dopaminergic receptors typically suppress prolactin PRL production and secretion; thus, a multitude of antipsychotics are associated with elevated serum PRL [ 2 ]. A retrospective study of psychiatric patients found that antipsychotic therapy was strongly associated with hyperprolactinemia [ 3 ], and that serum PRL levels were affected in a dose-dependent manner [ 4 , 5 , 6 ].
Once phosphorylated, STAT5 forms homodimers or heterodimerizes with another STAT family member, translocates to the nucleus, and transactivates its targets, which regulate alveolar differentiation and milk production and proliferation and apoptosis [ 7 ]. Transgenic or retrovirus-mediated expression of constitutively activated STAT5 in normal mammary epithelia in nulliparous mice causes alveolar differentiation and milk production [ 8 , 9 ]. Hyperprolactinemia associated with the use of antipsychotics of both classes often causes mammary swelling and lactation that are not associated with pregnancy [ 10 ].
However, we have also 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 ].
While it explains the dichotomous effects of early versus late-age pregnancy on breast cancer risk, the dual-role of PRL-JAK2-STAT5 in both promoting normal cell differentiation and suppressing the anticancer barrier in precancerous cells also predicts that hyperprolactinemia-inducing antipsychotics may have a similar dichotomous impact on breast tumorigenesis — reducing breast cancer risk when taken at a young age but increasing breast cancer risk if started at an older age or when early lesions have already been diagnosed.
However, when started at an early age, this type of medication is usually taken for decades or for lifetime [ 18 ], likely leading to protection against breast cancer earlier on but increased risk later in life. Therefore, epidemiological studies of breast cancer risk in patients on antipsychotics must consider hyperprolactinemia, starting age and length of treatment, precancerous lesion status, and multiple other confounding factors such as obesity and poor health status [ 2 , 19 , 20 , 21 , 22 , 23 ].
The limited work in this area has not stratified patients to consider all of these variables. Not surprisingly, these studies have resulted in inconclusive or contradictory reports [ 19 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ], although a few studies have detected a significant increase in breast cancer in women who were prescribed dopamine antagonists compared to age-matched controls who were not prescribed antipsychotics [ 32 , 33 ].
Data from well-controlled laboratory studies may provide the experimental foundation for sophisticated epidemiological studies that will involve multiple patient registries and are stringently controlled. Importantly, laboratory studies may especially expose potential cancer risk of administering hyperprolactinemia-inducing antipsychotics in patients who may have already developed precancerous lesions.
However, there have been no significant laboratory studies to investigate the influence of antipsychotics on breast cancer risk. Here, we report that in mouse models that closely mimic human breast cancer initiation, hyperprolactinemia-inducing antipsychotics accelerate early lesion progression to cancer via activation of JAK-STAT5 signaling to suppress the apoptosis anticancer barrier. These findings highlight the potential risk associated with the use of hyperprolactinemia-inducing antipsychotics in women at risk of breast cancer and urgently calls for epidemiological studies specifically designed to examine breast cancer risk in women who have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.
Briefly, lesion initiation is achieved by intraductal injection of a Rous sarcoma virus-based vector - replication-competent avian sarcoma RCAS - to deliver an oncogene into a minute subset of mammary epithelial cells in an otherwise normally developed mammary gland [ 34 ].
Five days later they were randomized and treated with either a drug or diluent for 2 weeks early lesion studies or until euthanasia tumor study. Mice in the tumor latency study were palpated thrice weekly and tumor size was recorded. When tumors reached 2. Pimozide cat. Risperidone cat. Aripiprazole cat. All drugs were diluted in dimethyl sulfoxide DMSO to the appropriate concentrations.
Both ruxolitinib and control chow was provided by Incyte Corp. Immunohistochemistry analysis IHC and immunofluorescence IF were performed as previously described [ 9 , 11 , 34 ]. Primary antibodies used included mouse monoclonal antibodies against HA ; cat. Asp; Cell Signaling , and Ki67 ; cat. MIB-1; Lycra. IF images were captured using the Zeiss Axiskop2 plus microscope.
For quantification of cells stained for a marker, 10 random fields of early lesions in each mammary gland were captured, and both positively stained cells and the total number of cells in the lesion as identified by DAPI or hematoxylin staining were counted to determine the percentage of positivity. ImageJ software was used for counting cells and determining lesion size.
The total numbers of cells in IF images were counted using a semi-automotive program that has been previously described [ 38 ]. Fixed thresholds were set to analyze both experimental and control mammary glands. DNA was extracted from the largest, left-most lobe of the lung. All numbers in this study are reported as medians and interquartile ranges in the format median IQR.
All tumor-free survival analyses were performed in R with the survival package using R commander interface. All other graphs were generated using Prism software.
Each dot in the dot plots generated for this study represents one mouse. We have reported a mouse model that closely mimics human breast cancer initiation and is ideally suited for studying hormones and other factors that may impact breast cancer risk [ 9 , 11 , 34 , 38 , 39 , 40 , 41 , 42 ]. The transgenic avian tva is only required for the initial virus infection; the virus does not replicate in mammalian cells.
Additionally, the oncogene is transcriptionally controlled by the proviral RCAS long terminal repeat LTR ; it is constitutively active and is not influenced by the presence of reproductive hormones such as prolactin [ 39 , 43 ]. Using this method, we explored the effect of several antipsychotics on mammary cancer development from preexisting early lesions.
Introduction of the oncogene took place before drug treatment so as to specifically investigate antipsychotic effects on preexisting precancerous early lesions rather than the overall risk that antipsychotics may pose on the normal mammary epithelia.
Mice were continually treated with either risperidone or the diluent control in drinking water for the duration of the study. When the tumor size reached 2. Tumors from both cohorts were high-grade, poorly differentiated, and highly mitotic with areas of necrosis. Many of the tumor cells were highly pleomorphic with large nuclei, often with metaplastic features. Therefore, we conclude that treatment with risperidone accelerates tumorigenesis and increases tumor multiplicity in mice with preexisting precancerous mammary lesions, while not influencing the grade, aggressiveness, or metastatic potential of the resulting tumors.
The chi square test was for used comparison. The Mann-Whitney test was used to determine the p values. Each dot in this plot represents one mouse. Five days following injection, mice were continually treated with risperidone or vehicle in their drinking water. Taken together, these data suggest that risperidone stimulates tumorigenesis initiated by multiple oncogenic events. We next determined if this tumorigenic acceleration was due to antipsychotic effects on early lesion development.
Early lesions were defined as any hyperplastic ductal foci comprised of three or more layers of epithelial cells stained positively for the provirus-encoded oncogene product HA tag. Risperidone-treated mice had more early lesions and higher early lesion burden than the vehicle control cohort Fig. Therefore, we conclude that risperidone promotes early lesion progression. Risperidone increases early lesion burden and lowers the level of apoptosis.
The p values were determined by the Mann-Whitney test. Each dot in these plots represents one mouse. To test whether the above-observed risperidone effect on mammary early lesions is broadly applicable across different subtypes of breast cancer, we administered risperidone or vehicle to mice transgenic for MMTV- Wnt1 [ 50 ], which develops basal-like tumors and some estrogen receptor ER -positive tumors [ 51 , 52 , 53 ].
Taken together, these data suggest that risperidone stimulates the progression of early lesions that are the precursor to multiple breast cancer subtypes. To determine the underlying mechanisms by which risperidone spurred early lesion expansion, we first compared the precancerous cell proliferation in these two cohorts of mice injected with RCAS-caErbB2. Besides cell proliferation, evasion of apoptosis serves a key role in the progression of precancerous early lesions to cancer [ 54 , 55 ].
We have reported that apoptosis was rapidly activated in mammary cells following ErbB2 activation to provide a barrier to cancer [ 11 , 42 , 44 ]. These results demonstrate that treatment with risperidone allows precancerous cells to suppress the apoptotic anticancer barrier to increase early lesion burden. Taken together, these data indicate that hyperprolactinemia-inducing antipsychotics dismantle the apoptosis anticancer barrier in early lesions and instigate their progression to cancer.
Together, we conclude that hyperprolactinemia-inducing antipsychotics cause preexisting early lesion to suppress the apoptosis anticancer barrier and to accelerate progression to cancer; these cancer-promoting effects are associated with hyperprolactinemia. To understand the underlying mechanism by which hyperprolactinemia-inducing antipsychotics suppress the apoptosis anticancer barrier and increase breast cancer risk, we asked whether treatment with risperidone activates the STAT5 signaling pathway.
Likewise, Bcl-xL was induced in early lesions Fig. Risperidone treatment increases signal transducer and activator of transcription 5 STAT5 activity. While 7. Of note, pimozide has been reported to block STAT5 activation in cultured cells [ 58 , 59 ], but this potential direct effect on STAT5 was overridden in vivo by hyperprolactinemia-induced PRL signaling. Together, these data suggest that hyperprolactinemia-inducing antipsychotics activate STAT5 and its transcriptional targets to suppress the apoptosis-anticancer barrier in preexisting precancerous cells, while simultaneously inducing alveolar differentiation in both early lesions and normal ducts.
We tested whether the gene encoding STAT5a, the predominant form of STAT5 in the mammary gland and tumorigenesis [ 35 , 61 ], is required for the above-observed effects of risperidone on early lesion progression, to investigate whether STAT5 activation is the crucial factor mediating antipsychotic stimulation of carcinogenesis.
This finding indicates that STAT5a plays a pivotal role in the effects of risperidone on evading the apoptotic anticancer barrier. Next, we examined whether STAT5 activity reduction also led to a lower early lesion burden in risperidone-treated mice. Taken together, these results demonstrate that STAT5 activity is responsible for evading the apoptosis anticancer barrier in early lesions and for instigating early lesion progression.
Genetic ablation of signal transducer and activator of transcription 5 STAT5 a dismantles the effects of risperidone on early lesions. The p values were determined by analysis of variance. Many older women on hyperprolactinemia-inducing antipsychotics may have already accumulated early lesions and subsequently may be at increased risk of breast cancer due to family history, older age, or other reasons.
Our aforementioned findings suggest that these antipsychotics likely also stimulate the progression of the early lesions in these high-risk women. Consequently, it is important to identify effective breast cancer preventive strategies in high-risk women who need to take these types of antipsychotics. There are currently only a few US Food and Drug Administrtion FDA -approved drugs for breast cancer chemoprevention, all of which antagonize estrogen signaling [ 62 ].
Therefore, we asked whether short-term ruxolitinib treatment could prevent mammary tumors in early lesion-bearing mice on risperidone.