Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs

Rahman, Tahir; Sahrmann, John M.; Olsen, Margaret A.; Nickel, Katelin B.; Miller, J. Phillip; Ma, Cynthia; Grucza, Richard A.

doi:10.1097/jcp.0000000000001513

Cited by 32 publications

(45 citation statements)

References 39 publications

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“…Antipsychotics that act by antagonizing dopamine, thereby raising circulating PRL, promoted tumorigenesis in experimental models initiated by RCAS-caErbB2, RCAS-HrasQ61L and MMTV-Wnt-1 ( 97 ). A recent study found that patients using these drugs had a significantly increased risk of breast cancer ( 20 ). Together, these observations in patients and murine models indicate a role(s) for PRL in progression of early lesions.…”

Section: Prl Actions In Development Of Breast Cancermentioning

confidence: 99%

“…Pituitary PRL secretion is influenced by many factors, and circulating levels in nonpregnant women vary considerably ( 16 – 18 ). In addition to physiological stimuli, estrogen-progestin menopausal hormone therapy (MHT) raises circulating PRL ( 18 ), and anti-psychotics that antagonize dopamine induce hyperprolactinemia ( 19 , 20 ). Further, PRL also can be expressed by non-lactotrophs, including within the mammary gland ( 21 – 23 ), and by breast cancer cells themselves ( 24 – 27 ).…”

Section: Introductionmentioning

confidence: 99%

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Prolactin: The Third Hormone in Breast Cancer

Schuler

O’Leary

2022

Front. Endocrinol.

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Prolactin coordinates with the ovarian steroids to orchestrate mammary development and lactation, culminating in nourishment and an increasingly appreciated array of other benefits for neonates. Its central activities in mammary epithelial growth and differentiation suggest that it plays a role(s) in breast cancer, but it has been challenging to identify its contributions, essential for incorporation into prevention and treatment approaches. Large prospective epidemiologic studies have linked higher prolactin exposure to increased risk, particularly for ER+ breast cancer in postmenopausal women. However, it has been more difficult to determine its actions and clinical consequences in established tumors. Here we review experimental data implicating multiple mechanisms by which prolactin may increase the risk of breast cancer. We then consider the evidence for role(s) of prolactin and its downstream signaling cascades in disease progression and treatment responses, and discuss how new approaches are beginning to illuminate the biology behind the seemingly conflicting epidemiologic and experimental studies of prolactin actions across diverse breast cancers.

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Section: Prl Actions In Development Of Breast Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prolactin: The Third Hormone in Breast Cancer

Schuler

O’Leary

2022

Front. Endocrinol.

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“…All nine studies defined the outcome of interest as the first-time diagnosis of breast cancer, with five studies specifying the adopted diagnosis explicitly based on International Classification of Diseases (ICD) (Wang et al, 2002;Chou et al, 2017;Pottegård et al, 2018;Taipale et al, 2021;Rahman et al, 2022), one of which also identified first claims of breast cancer surgeries without an ICD code diagnosis as cases (Wang et al, 2002). Either surgery, chemotherapy or hospitalisation for breast cancer in addition to the diagnosis with ICD code was adopted for one study (Rahman et al, 2022) (Wang et al, 2002;Chou et al, 2017;Pottegård et al, 2018;Taipale et al, 2021;Rahman et al, 2022) that specified the diagnosis based on ICD codes supported the association. From the remaining studies that received quality assessment scores ranging from seven to nine stars (Mortensen, 1987;Dalton et al, 2006;Hippisley-Cox et al, 2007;Chou et al, 2017;George et al, 2020), both association and non-association were observed.…”

Section: Outcomebreast Cancermentioning

confidence: 99%

“…They reported HRs 2.49 (95% CI 1.69-3.66) and 1.05 (95% CI 0.58-1.87) for mean antipsychotic exposure of less than 28 and greater than 245 g/year, respectively. Some studies have also investigated the prolactin-elevating properties of antipsychotics and its association with breast cancer development (Chou et al, 2017;Pottegård et al, 2018;Taipale et al, 2021;Rahman et al, 2022). Exposure to antipsychotics with prolactin-elevating properties were included in Pottegård et al (2018), to which long-term exposure showed an increased risk of breast cancer.…”

Section: Exposureantipsychotic Usementioning

confidence: 99%

Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals

Leung

Chu

et al. 2022

Epidemiol Psychiatr Sci

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Aims Despite reports of an elevated risk of breast cancer associated with antipsychotic use in women, existing evidence remains inconclusive. We aimed to examine existing observational data in the literature and determine this hypothesised association. Methods We searched Embase, PubMed and Web of Science™ databases on 27 January 2022 for articles reporting relevant cohort or case-control studies published since inception, supplemented with hand searches of the reference lists of the included articles. Quality of studies was assessed using the Newcastle-Ottawa Scale. We generated the pooled odds ratio (OR) and pooled hazard ratio (HR) using a random-effects model to quantify the association. This study was registered with PROSPERO (CRD42022307913). Results Nine observational studies, including five cohort and four case-control studies, were eventually included for review (N = 2 031 380) and seven for meta-analysis (N = 1 557 013). All included studies were rated as high-quality (seven to nine stars). Six studies reported a significant association of antipsychotic use with breast cancer, and a stronger association was reported when a greater extent of antipsychotic use, e.g. longer duration, was operationalised as the exposure. Pooled estimates of HRs extracted from cohort studies and ORs from case-control studies were 1.39 [95% confidence interval (CI) 1.11–1.73] and 1.37 (95% CI 0.90–2.09), suggesting a moderate association of antipsychotic use with breast cancer. Conclusions Antipsychotic use is moderately associated with breast cancer, possibly mediated by prolactin-elevating properties of certain medications. This risk should be weighed against the potential treatment effects for a balanced prescription decision.

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“…Furthermore, emerging evidence shows that prolactin has protumor properties in breast, prostate, colorectal, liver, ovarian, and endometrial cancers [14]. Recently, several epidemiological studies showed that prolactin-elevating antipsychotics increase the risk of breast cancer and breast cancer-specific mortality [15][16][17]. Therefore, more attention is needed to dissect the role of antipsychotics in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade

Chiang

Lei

Chang

et al. 2022

Cancers

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Haloperidol is a routine drug for schizophrenia and palliative care of cancer; it also has antitumor effects in several types of cancer. However, the role of haloperidol in endometrial cancer (EC) development is still unclear. Here, we show that chronic haloperidol treatment in clinically relevant doses induced endometrial hyperplasia in normal mice and promoted tumor growth and malignancy in mice with orthotopic EC. The pharmacokinetic study indicated that haloperidol highly accumulated in the uterus of mice. In vitro studies revealed that haloperidol stimulated the cellular transformation of human endometrial epithelial cells (HECCs) and promoted the proliferation, migration, and invasion of human endometrial carcinoma cells (HECCs) by activating nuclear factor kappa B (NF-κB) and its downstream signaling target, colony-stimulating factor 1 (CSF-1). Gain of function of CSF-1 promotes the cellular transformation of HEECs and the malignant progression of HECCs. Moreover, blockade of CSF-1 inhibited haloperidol-promoted EC progression in vitro and in vivo. A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.

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Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs

Cited by 32 publications

References 39 publications

Prolactin: The Third Hormone in Breast Cancer

Prolactin: The Third Hormone in Breast Cancer

Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals

Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade

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