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: Anna Di Benedetto, Marcella Mottolese, Francesca Sperati, Cristiana Ercolani, Luigi Di Lauro, Laura Pizzuti, Patrizia Vici, Irene Terrenato, Abeer M Shaaban, Sreekumar Sundara-Rajan, Matthew P Humphries, Maddalena Barba, Valerie Speirs, Ruggero De Maria, Marcello Maugeri-Saccà
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 35121 (10 07 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27713571 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Intracellular Signaling Peptides and Proteins
• Phosphoproteins
• Receptors, Androgen
• Receptors, Estrogen
• Receptors, Progesterone
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• YAP-Signaling Proteins
• YAP1 protein, human
• Cholesterol
• Hydroxymethylglutaryl CoA Reductases
• Protein Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis)
• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms, Male (mortality, pathology)
• Cholesterol (biosynthesis)
• Gene Expression Regulation, Neoplastic
• Hippo Signaling Pathway
• Humans
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Intracellular Signaling Peptides and Proteins (biosynthesis)
• Male
• Middle Aged
• Phosphoproteins (biosynthesis)
• Protein Serine-Threonine Kinases (biosynthesis)
• Receptors, Androgen (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Retrospective Studies
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• Treatment Outcome
• YAP-Signaling Proteins