HMG-CoAR expression in male breast cancer: relationship with hormone receptors, Hippo transducers and survival outcomes

Sci Rep. 2016 Oct 7:6:35121. doi: 10.1038/srep35121.

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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms, Male / mortality
  • Breast Neoplasms, Male / 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

Substances

  • 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