title: HMG-CoAR expression in male breast cancer: relationship with hormone receptors, Hippo transducers and survival outcomes.
abstract: Male breast cancer (MBC) is a rare hormone-driven disease often associated with obesity. HMG-CoAR is the central enzyme of the mevalonate pathway, a molecular route deputed to produce cholesterol and steroid-based hormones. HMG-CoAR regulates the oncogenic Hippo transducers TAZ/YAP whose expression was previously associated with shorter survival in MBC. 225 MBC samples were immunostained for HMG-CoAR and 124 were considered eligible for exploring its relationship with hormone receptors (ER, PgR, AR), Hippo transducers and survival outcomes. HMG-CoAR was positively associated with the expression of hormone receptors (ER, PgR, AR) and Hippo transducers. Overall survival was longer in patients with HMG-CoAR-positive tumors compared with their negative counterparts (p = 0.031). Five- and 10-year survival outcomes were better in patients whose tumors expressed HMG-CoAR (p = 0.044 and p = 0.043). Uni- and multivariate analyses for 10-year survival suggested that HMG-CoAR expression is a protective factor (HR 0.50, 95% CI: 0.25-0.99, p = 0.048 and HR 0.53, 95% CI: 0.26-1.07, p = 0.078). Results were confirmed in a sensitivity analysis by excluding uncommon histotypes (multivariate Cox: HR 0.45, 95% CI: 0.21-0.97, p = 0.043). A positive relationship emerged between HMG-CoAR, hormone receptors and TAZ/YAP, suggesting a connection between the mevalonate pathway, the hormonal milieu and Hippo in MBC. Moreover, HMG-CoAR expression may be a favorable prognostic indicator.
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Benedetto
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.affiliation: Department of Pathology, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Ercolani
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Di Lauro
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pizzuti
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Biostatistics-Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Queen Elizabeth Hospital Birmingham and University of Birmingham, Department of Histopathology, Edgbaston, Birmingham B15 2GW, UK.
authors.forename: Abeer M
authors.initials: AM
authors.lastname: Shaaban
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Sundara-Rajan
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Humphries
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Institute of General Pathology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 10, 00168, Rome.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Division of Medical Oncology B, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.|Scientific Direction, "Regina Elena" National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Maugeri-Saccà
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018567:Breast Neoplasms, Male / Q000401:mortality / Q000473:pathology*; D002784:Cholesterol / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012189:Retrospective Studies; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D016896:Treatment Outcome; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D017346:Protein Serine-Threonine Kinases