ONCOmmunity

Unraveling the Role of Huntingtin in Breast Cancer Metastasis.

By: Morgane S Thion, John R McGuire, Cristovao M Sousa, Laetitia Fuhrmann, Julien Fitamant, Sophie Leboucher, Sophie Vacher, Sophie Tezenas du Montcel, Ivan Bièche, Agnès Bernet, Patrick Mehlen, Anne Vincent-Salomon, Sandrine Humbert

Institut Curie, Paris, France (MST, JRM, CMS, LF, SL, SV, IB, AVS, SH); CNRS UMR 3306, Orsay, France (MST, JRM, CMS, SL, SH); INSERM U1005, Orsay, France (MST, JRM, CMS, SL, SH); University Paris Sud 11, Orsay, France (MST); Apoptosis, Cancer and Development Laboratory, Equipe labellisée 'La Ligue', Centre National de la Recherche Scientifique UMR5238, Université de Lyon, Lyon, France (JF, AB, PM); Department of Biostatistics and Medical Informatics, Assistance Publique-Hôpitaux de Paris (STdM); Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France (STdM); INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France (STdM); University Paris Descartes, Sorbonne Paris Cité, France (IB); Department of Pathology, Institut Curie, Paris, France (AVS); Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France (SH); INSERM U836, Grenoble, France (SH).
2014-11-19; doi: 10.1093/jnci/djv208

Abstract

Background

Huntingtin (HTT) is mutated in Huntington's disease but is ubiquitously expressed, and mutant HTT influences cancer progression. We investigated wild-type HTT function during breast cancer.

Methods

We analyzed HTT and ZO1 expression as well as the HTT phosphoserine 421-activated form (S421-P-HTT) in human breast cancer tissues by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. We performed in vitro migration and invasion assays as well as in vivo tail vein injections of the metastatic 4T1 cells in BALB/c mice (n = 11 per group). We analyzed tumor progression in knock-in mice with modified S421 crossed with the MMTV-PyVT mammary cancer model (at least n = 12 per group). Data were analyzed with unpaired t tests, analysis of variance, Pearson or Spearman correlation, and Mann Whitney or Kruskal-Wallis tests. All statistical tests were two-sided.

Results

Levels of HTT and of S421-P-HTT are abnormally low in poorly differentiated and metastatic human breast cancers. HTT expression is downregulated in invasive compared with in situ carcinoma (P < .001). In BALB/c mice, silencing of HTT promotes lung colonization by a metastatic mammary cancer cell line (P = .005) and S421-unphosphorylatable-HTT accelerates cancer progression. HTT interacts with ZO1 and regulates both its expression and its localization to tight junctions. In human breast tumors, the patterns of HTT and ZO1 expression are similar (Pearson correlation coefficient = 0.66, P < .001).

Conclusions

HTT may inhibit breast tumor dissemination through maintenance of ZO1 at tight junctions. Downregulation of HTT transcript and protein levels is a prognostic factor for poor prognosis and metastasis development.