Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy.

Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.

mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions.

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

Immunomodulatory role of decidual prolactin on the human fetal membranes and placenta.

The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface.

Prolactin Regulates Testicular Gene Expression and Cell Cycle Processes Predominantly via JAK2/STAT5 Pathway in the Male Rat.

Hyperprolactinemia is prevalent in up to 16% of infertile males. Although the prolactin receptor (PRLR) is present on various testicular cells, the physiological role of this receptor in spermatogenesis remains elusive. The aim of this study is to delineate prolactin actions in rat testicular tissue. Serum prolactin, developmental expression of PRLR, signaling pathways associated, and gene transcription regulation in the testes were investigated. Serum prolactin and testicular PRLR expression was found to be significantly increased at pubertal and adult ages as compared to prepubertal. Further, PRLR activated the JAK2/STAT5 pathway, but not the MAPK/ERK and PI3K/AKT pathway in the testicular cells. Gene expression profiling following prolactin treatment in seminiferous tubule culture resulted in a total of 692 differentially expressed genes, of which 405 were upregulated and 287 were downregulated. Enrichment map analysis showed that prolactin target genes are involved in processes such as cell cycle, male reproduction, chromatin remodeling, and cytoskeletal organization. Novel gene targets of prolactin whose role in testes is unexplored were obtained and validated by qPCR. Additionally, 10 genes involved in cell cycle process were also validated; 6 genes (Ccna1, Ccnb1, Ccnb2, Cdc25a, Cdc27, Plk1) were found to be significantly upregulated, whereas 4 genes (Ccar2, Nudc, Tuba1c, Tubb2a) were found to be significantly downregulated in testes after treatment with prolactin. Taken together, the findings from this study suggest a crucial role of prolactin in male reproduction and identified target genes regulated by prolactin in the testes.

[Prostatic luminal progenitors: From tissue regeneration to therapeutic escape]. / Progéniteurs luminaux prostatiques - De la régénération tissulaire à la résistance thérapeutique.

Inhibition of androgen signaling is the gold standard treatment of benign prostate hyperplasia and prostate cancer. Despite the initial response to these treatments, therapeutic resistance is ultimately observed in most patients. Single cell RNAseq studies have shown that castration-tolerant luminal cells share several molecular and functional features with cells identified as luminal progenitor in physiological conditions. The increased prevalence of luminal progenitor-like cells in tumor contexts might result from their intrinsic androgen-independence and from the reprogramming of differentiated luminal cells into a castration-tolerant state. Thus, it is currently hypothesized that the luminal progenitor molecular profile might constitute a functional hub for cell survival in androgen deprivation context, a prerequisite for tumor regrowth. Therapeutic intervention interfering with luminal lineage plasticity is a promising approach to prevent prostate cancer progression.

Title: Progéniteurs luminaux prostatiques - De la régénération tissulaire à la résistance thérapeutique. Abstract: Les traitements médicaux de l'hyperplasie bénigne et du cancer de la prostate reposent essentiellement sur l'inhibition de la signalisation androgénique. Bien qu'initialement efficaces, ces traitements sont tôt ou tard confrontés à une résistance thérapeutique. Des données récentes de séquençage d'ARN sur cellules uniques montrent que les cellules luminales survivant à la déprivation androgénique dans ces contextes pathologiques présentent un profil moléculaire semblable à celui de cellules luminales progénitrices, présentes en faible quantité dans un contexte physiologique. Ce profil moléculaire pourrait constituer un hub de résistance à la castration et résulter, en partie, de la reprogrammation des cellules luminales tumorales. L'inhibition thérapeutique de cette plasticité cellulaire constitue une piste prometteuse pour limiter la progression du cancer prostatique.

Transcriptomic Signature and Growth Factor Regulation of Castration-Tolerant Prostate Luminal Progenitor Cells.

Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSCmed cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSCmed cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSCmed cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSCmed cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSCmed marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSCmed cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSCmed cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.

Identification of growth hormone receptor as a relevant target for precision medicine in low-EGFR expressing glioblastoma.

OBJECTIVE: New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. METHODS: With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We then conducted gain of function as well as genetic and pharmocological inhibition assays in GBM patient-derived cell lines to functionnally validate our finding. RESULTS: We identified that growth hormone receptor (GHR) signalling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of suppressor of cytokine signalling 2 (SOCS2) expression due to SOCS2 promoter hypermethylation. In GBM patient-derived cell lines, GHR signalling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro and promotes tumourigenesis, tumour growth, and tumour invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. CONCLUSION: This study pioneers a new field of investigation to improve the prognosis of GBM patients.

High Keratin-7 Expression in Benign Peri-Tumoral Prostatic Glands Is Predictive of Bone Metastasis Onset and Prostate Cancer-Specific Mortality.

BACKGROUND: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in the mouse prostate. METHODS: KRT7 expression was evaluated in prostatic cell lines and in human tissue by immunohistochemistry (IHC, on advanced PC, n = 91) and immunofluorescence (IF, on localized PC, n = 285). The KRT7 mean fluorescence intensity (MFI) was quantified in different compartments by digital analysis and correlated to clinical endpoints in the localized PC cohort. RESULTS: KRT7 is expressed in prostatic cell lines and found in the basal and supra-basal compartment from healthy prostatic glands and benign peri-tumoral glands from localized PC. The KRT7 staining is lost in luminal cells from localized tumors and found as an aberrant sporadic staining (2.2%) in advanced PC. In the localized PC cohort, high KRT7 MFI above the 80th percentile in the basal compartment was significantly and independently correlated with MFS and CSS, and with hypertrophic basal cell phenotype. CONCLUSION: High KRT7 expression in benign glands is an independent biomarker of MFS and CSS, and its expression is lost in tumoral cells. These results require further validation on larger cohorts.

Prostate luminal progenitor cells: from mouse to human, from health to disease.

Stem and progenitor cells of the adult prostate epithelium have historically been believed to reside mainly or exclusively within the basal cell compartment and to possess basal-like phenotypic characteristics. Within the past decade, evidence of the existence of luminal epithelial cells exhibiting stem/progenitor properties has been obtained by lineage tracing and by functional characterization of sorted luminal-like cells. In 2020, the boom of single-cell transcriptomics led to increasingly exhaustive profiling of putative mouse luminal progenitor cells and, importantly, to the identification of cognate cells in the human prostate. The enrichment of luminal progenitor cells in genetically modified mouse models of prostate inflammation, benign prostate hypertrophy and prostate cancer, and the intrinsic castration tolerance of these cells, suggest their potential role in prostate pathogenesis and in resistance to androgen deprivation therapy. This Review bridges different approaches that have been used in the field to characterize luminal progenitor cells, including the unification of multiple identifiers employed to define these cells (names and markers). It also provides an overview of the intrinsic functional properties of luminal progenitor cells, and addresses their relevance in mouse and human prostate pathophysiology.

Sex-dependent pain trajectories induced by prolactin require an inflammatory response for pain resolution.

Pain development and resolution patterns in many diseases are sex-dependent. This study aimed to develop pain models with sex-dependent resolution trajectories, and identify factors linked to resolution of pain in females and males. Using different intra-plantar (i.pl.) treatment protocols with prolactin (PRL), we established models with distinct, sex-dependent patterns for development and resolution of pain. An acute PRL-evoked pain trajectory, in which hypersensitivity is fully resolved within 1 day, showed substantial transcriptional changes after pain-resolution in female and male hindpaws and in the dorsal root ganglia (DRG). This finding supports the notion that pain resolution is an active process. Prolonged treatment with PRL high dose (1 µg) evoked mechanical hypersensitivity that resolved within 5-7 days in mice of both sexes and exhibited a pro-inflammatory transcriptional response in the hindpaw, but not DRG, at the time point preceding resolution. Flow cytometry analysis linked pro-inflammatory responses in female hindpaws to macrophages/monocytes, especially CD11b+/CD64+/MHCII+ cell accumulation. Prolonged low dose PRL (0.1 µg) treatment caused non-resolving mechanical hypersensitivity only in females. This effect was independent of sensory neuronal PRLR and was associated with a lack of immune response in the hindpaw, although many genes underlying tissue damage were affected. We conclude that different i.pl. PRL treatment protocols generates distinct, sex-specific pain hypersensitivity resolution patterns. PRL-induced pain resolution is preceded by a pro-inflammatory macrophage/monocyte-associated response in the hindpaws of mice of both sexes. On the other hand, the absence of a peripheral inflammatory response creates a permissive condition for PRL-induced pain persistency in females.

Hematopoietic PBX-interacting protein is a novel regulator of mammary epithelial cell differentiation.

Hematopoietic PBX-interacting protein (HPIP, also known as PBXIP1) is an estrogen receptor (ER) interacting protein that regulates estrogen-mediated breast cancer cell proliferation and tumorigenesis. However, its functional significance in the context of mammary gland development is unexplored. Here, we report that HPIP is required for prolactin (PRL)-induced lactogenic differentiation in vitro. Molecular analysis of HPIP expression in mice revealed its induced expression at pregnancy and lactation stages of mammary gland. Moreover, PRL is a lactogenic hormone that controls pregnancy as well as lactation and induces Hpip/Pbxip1 expression in a signal transducer and activator of transcription 5a-dependent manner. Using mammary epithelial and lactogenic-competent cell lines, we further show that HPIP plays a regulatory role in PRL-mediated mammary epithelial cell differentiation, which is measured by acini formation, ß-casein synthesis, and lipid droplet formation. Further mechanistic studies using pharmacological inhibitors revealed that HPIP modulates PRL-induced ß-casein synthesis via phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) activation. This study also identified HPIP as a critical regulator of autocrine PRL signaling as treatment with the PRL receptor antagonist Δ1-9-G129R-hPRL restrained HPIP-mediated PRL synthesis, AKT activation, and ß-casein synthesis in cultured HC11 cells. Interestingly, we also uncovered that microRNA-148a (miR-148a) antagonizes HPIP-mediated mammary epithelial cell differentiation. Together, our study identified HPIP as a critical regulator of PRL signaling and revealed a novel molecular circuitry involving PRL, HPIP, PI3K/AKT, and miR-148a that controls mammary epithelial cell differentiation in vitro.

STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway.

STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability, potentiating antitumor immune responses. Here we report that STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in a panel of breast cancer cell lines in a cell-autonomous manner. STING silencing impaired DNA Damage Response (53BP1) foci formation and increased DNA break accumulation. These newly identified properties were found to be independent of STING partner cGAS and of its canonical pro-inflammatory pathway. STING was shown to partially localize at the inner nuclear membrane in a variety of breast cancer cell models and clinical tumor samples. Interactomics analysis of nuclear STING identified several proteins of the DNA Damage Response, including the three proteins of the DNA-PK complex, further supporting a role of STING in the regulation of genomic stability. In breast and ovarian cancer patients that received adjuvant chemotherapy, high STING expression is associated with increased risk of relapse. In summary, this study highlights an alternative, non-canonical tumor-promoting role of STING that opposes its well-documented function in tumor immunosurveillance.

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: Results of the FOSTINE trial.

OBJECTIVE: To assess the feasibility, safety and precision of organ-based tracking (OBT)-fusion targeted focal microwave ablation (FMA), in patients with low to intermediate risk prostate cancer. PATIENTS AND METHOD: Ten patients with a visible index tumor of Gleason score ≤3+4, largest diameter <20mm were included. Transrectal OBT-fusion targeted FMA was performed using an 18G needle. Primary endpoint was the evidence of complete overlap of the index tumor by ablation zone necrosis on MRI 7 days after ablation. Urinary and sexual function were assessed with IPSS, IIEF5 and MSHQ-EjD-SF. Oncological outcomes were assessed with PSA at 2 and 6 months, and re-biopsy at 6 months. RESULTS: Median [IQR] age was 64.5 [61-72] years and baseline PSA was 5 [4.3-8.1] ng/mL. Seven (70%) and 3 (30%) patients had a low and intermediate risk cancer, respectively. Median largest tumor axis was of 11 [9.0-15.0] mm. Median duration of procedure was of 82 [44-170] min. No patient reported any pain or rectal bleeding, and all 10 patients were discharged the next day. Seven days after ablation, total necrosis of the index tumor on MRI was obtained in eight (80% [95%CI 55%-100%]) patients. One patient was treated with radical prostatectomy. Re-biopsy at 6 months in the other 9 did not show evidence of cancer in 4 patients. IPSS, IIEF-5 and MSHQ-EjD-SF were not statistically different between baseline and 6 months follow up. CONCLUSIONS: OBT-fusion targeted FMA was feasible, precise, and safe in patients with low to intermediate risk localized prostate cancer.

Meningeal CGRP-Prolactin Interaction Evokes Female-Specific Migraine Behavior.

OBJECTIVE: Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female-specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. METHODS: Prolactin, CGRP, and receptor antagonists CGRP8-37 or Δ1-9-G129R-hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back-labeled trigeminal ganglia (TG) neurons was used to assess PRL-induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. RESULTS: We found that dural PRL produced sustained and long-lasting migraine-like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little-to-no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8-37 decreases migraine-like responses to dural PRL. Reciprocally, Δ1-9-G129R-hPRL attenuates dural CGRP-induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine-like responses to dural CGRP. INTERPRETATION: This CGRP-PRL interaction in the meninges is a mechanism by which these peptides could produce female-selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129-1144.

Neuroendocrine Mechanisms Governing Sex Differences in Hyperalgesic Priming Involve Prolactin Receptor Sensory Neuron Signaling.

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

Positive association between progestins and the evolution of multiple fibroadenomas in 72 women.

OBJECTIVE: Multiple fibroadenomas (MFA) of the breast is a rare benign disease, thus its natural history is poorly understood. The aim of our study was to describe the radiological evolution of MFA and to evaluate the influence of different factors on this evolution. METHODS: This was a longitudinal cohort study. All patients included had two clinical and radiological assessments (breast ultrasound (US) and/or MRI) at least 5 years apart. RESULTS: Seventy-two women were followed for 7.6 ± 2.1 years. The radiological evolution showed a decrease or stability in the number of fibroadenomas (FA) in 26/44 cases on the MRI and in 38/64 cases on the US. There was a decrease of size in 35/44 cases on the MRI and in 53/64 cases on the US. An increase in the number of FAs was found in 18/44 cases in the MRI and 26/64 cases in the US with, for the majority, a decrease of size (19/26 by MRI and 16/18 by MRI). Older age at the first FA (P < 0.0001) and at the diagnosis of MFA (P < 0.0001), pregnancy (P = 0.003) and progestin use (P < 0.001), particularly lynestrenol (P < 0.0001), had a beneficial effect on the evolution of MFA. CONCLUSION: This is the first longitudinal study describing women with MFA. The radiological evolution of MFA seamed favorable and similar to that expected for a single FA. We identified factors influencing the evolution of the disease, including progestin treatments such as lynestrenol, which could have a beneficial effect. Our cohort should be followed further in order to expand our knowledge of MFA, especially concerning the risk of breast cancer.

Prolactin and its receptor as therapeutic targets in glioblastoma multiforme.

Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1-9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL+/PRLRHIGH GBM performed worse than PRL+/PRLRLOW GBM. In contrast, all male PRL+/PRLRHIGH GII-III patients were alive whereas only 30% of PRL+/PRLRLOW GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.

Author Correction: Collagen XXV promotes myoblast fusion during myogenic differentiation and muscle formation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.