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

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

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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.

Original languageEnglish
Article number35121
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 7 Oct 2016

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms, Male
  • Cholesterol
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hydroxymethylglutaryl CoA Reductases
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Phosphoproteins
  • Protein-Serine-Threonine Kinases
  • Receptors, Androgen
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Retrospective Studies
  • Treatment Outcome
  • Journal Article

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    Di Benedetto, A., Mottolese, M., Sperati, F., Ercolani, C., Di Lauro, L., Pizzuti, L., Vici, P., Terrenato, I., Shaaban, A. M., Sundara-Rajan, S., Humphries, M. P., Barba, M., Speirs, V., De Maria, R., & Maugeri-Saccà, M. (2016). HMG-CoAR expression in male breast cancer: relationship with hormone receptors, Hippo transducers and survival outcomes. Scientific Reports, 6, [35121]. https://doi.org/10.1038/srep35121