The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers

Ramírez-de-Arellano, Adrián; Villegas-Pineda, Julio César; Hernández-Silva, Christian David; Pereira-Suárez, Ana Laura

doi:10.3389/fendo.2021.747810

Cited by 17 publications

(14 citation statements)

References 102 publications

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“…PRL is a circulating pituitary polypeptide hormone, measurable in healthy women without any ovarian pathology at levels partially overlapping the ranges obtained in this study. Although the main source of the circulating PRL are hypophyseal lactotrophic cells and its best recognized physiological role is the regulation of implantation, pregnancy, lactation and sexual response, PRL is also synthesized at several sites outside the pituitary, e.g., the endometrium, myometrium, decidua, immune cells, brain, breast, prostate, skin, and adipose tissue, where it is involved in neuromodulation, immunoregulation, angiogenesis, cell proliferation and differentiation [ 56 ]. In gynecologic cancers, PRL exhibits antiapoptotic and pro-tumoral properties by promoting tumor cell migration, invasion, metastasis, and chemoresistance via various signaling pathways and effector proteins [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

Watrowski

Obermayr

Wallisch

et al. 2022

Cancers

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Ovarian cancer (OC) is the most lethal genital malignancy in women. We aimed to develop and validate new proteomic-based models for non-invasive diagnosis of OC. We also compared them to the modified Risk of Ovarian Malignancy Algorithm (ROMA-50), the Copenhagen Index (CPH-I) and our earlier Proteomic Model 2017. Biomarkers were assessed using bead-based multiplex technology (Luminex®) in 356 women (250 with malignant and 106 with benign ovarian tumors) from five European centers. The training cohort included 279 women from three centers, and the validation cohort 77 women from two other centers. Of six previously studied serum proteins (CA125, HE4, osteopontin [OPN], prolactin, leptin, and macrophage migration inhibitory factor [MIF]), four contributed significantly to the Proteomic Model 2021 (CA125, OPN, prolactin, MIF), while leptin and HE4 were omitted by the algorithm. The Proteomic Model 2021 revealed a c-index of 0.98 (95% CI 0.96, 0.99) in the training cohort; however, in the validation cohort it only achieved a c-index of 0.82 (95% CI 0.72, 0.91). Adding patient age to the Proteomic Model 2021 constituted the Combined Model 2021, with a c-index of 0.99 (95% CI 0.97, 1) in the training cohort and a c-index of 0.86 (95% CI 0.78, 0.95) in the validation cohort. The Full Combined Model 2021 (all six proteins with age) yielded a c-index of 0.98 (95% CI 0.97, 0.99) in the training cohort and a c-index of 0.89 (95% CI 0.81, 0.97) in the validation cohort. The validation of our previous Proteomic Model 2017, as well as the ROMA-50 and CPH-I revealed a c-index of 0.9 (95% CI 0.82, 0.97), 0.54 (95% CI 0.38, 0.69) and 0.92 (95% CI 0.85, 0.98), respectively. In postmenopausal women, the three newly developed models all achieved a specificity of 1.00, a positive predictive value (PPV) of 1.00, and a sensitivity of >0.9. Performance in women under 50 years of age (c-index below 0.6) or with normal CA125 (c-index close to 0.5) was poor. CA125 and OPN had the best discriminating power as single markers. In summary, the CPH-I, the two combined 2021 Models, and the Proteomic Model 2017 showed satisfactory diagnostic accuracies, with no clear superiority of either model. Notably, although combining values of only four proteins with age, the Combined Model 2021 performed comparably to the Full Combined Model 2021. The models confirmed their exceptional diagnostic performance in women aged ≥50. All models outperformed the ROMA-50.

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Section: Discussionmentioning

confidence: 99%

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

Watrowski

Obermayr

Wallisch

et al. 2022

Cancers

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“…Several mechanisms have been hypothesized to justify the carcinogenic capabilities of antipsychotics. There is increasing evidence that elevated prolactin, via the hypothalamic dopamine system and perhaps pituitary dopamine receptors, could be the instigator for some antipsychotics-induced EC [36,37]. Nevertheless, the epidemiological relationship between antipsychotics-mediated hyperprolactinemia and EC is limited and conflicting [20,38].…”

Section: Discussionmentioning

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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“…First, the gene family analysis tool at GSEA website (http://www.gsea-msigdb.org/) [30] notably identified prolactin (PRL) gene was positively correlated with DSCAM-AS1, coding for a hormone being a highly potent driver of endometrial cancer development and progression (R = 0.497, p = 2.41 × 10 −8 ) (reviewed in [32]). Corroborating the significance of this correlation, DSCAM-AS1 was also associated with expression of PRLH gene coding for the prolactin releasing hormone (R = 0.503, p = 1.53 × 10 −8 ).…”

Section: Genes Correlated With Dscam-as1 In Endometrial Adenocarcinomamentioning

confidence: 99%

DSCAM-AS1 Long Non-Coding RNA Exerts Oncogenic Functions in Endometrial Adenocarcinoma via Activation of a Tumor-Promoting Transcriptome Profile

Treeck¹,

Weber

Fritsch³

et al. 2022

Biomedicines

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Accumulating evidence suggests that lncRNA DSCAM-AS1 acts tumor-promoting in various cancer entities. In breast cancer, DSCAM-AS1 was shown to be the lncRNA being most responsive to induction by estrogen receptor α (ERα). In this study, we examined the function of DSCAM-AS1 in endometrial adenocarcinoma using in silico and different in vitro approaches. Initial analysis of open-source data revealed DSCAM-AS1 overexpression in endometrial cancer (EC) (p < 0.01) and a significant association with shorter overall survival of EC patients (HR = 1.78, p < 0.01). In EC, DSCAM-AS1 was associated with endometrial tumor promotor gene PRL and with expression of ERα and its target genes TFF1 and PGR. Silencing of this lncRNA by RNAi in two EC cell lines was more efficient in ERα-negative HEC-1B cells and reduced their growth and the expression of proliferation activators like NOTCH1, PTK2 and EGR1. DSCAM-AS1 knockdown triggered an anti-tumoral transcriptome response as revealed by Affymetrix microarray analysis, emerging from down-regulation of tumor-promoting genes and induction of tumor-suppressive networks. Finally, several genes regulated upon DSCAM-AS1 silencing in vitro were found to be inversely correlated with this lncRNA in EC tissues. This study clearly suggests an oncogenic function of DSCAM-AS1 in endometrial adenocarcinoma via activation of a tumor-promoting transcriptome profile.

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The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers

Cited by 17 publications

References 102 publications

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

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

DSCAM-AS1 Long Non-Coding RNA Exerts Oncogenic Functions in Endometrial Adenocarcinoma via Activation of a Tumor-Promoting Transcriptome Profile

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