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High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.

Authors
  • Desai, Krisha1
  • Nair, Madhumathy G1
  • Prabhu, Jyothi S1
  • Vinod, Anupama1
  • Korlimarla, Aruna1
  • Rajarajan, Savitha1
  • Aiyappa, Radhika1
  • Kaluve, Rohini S1
  • Alexander, Annie1
  • Hari, P S1
  • Mukherjee, Geetashree2
  • Kumar, Rekha V2
  • Manjunath, Suraj3
  • Correa, Marjorrie3
  • Srinath, B S4
  • Patil, Shekhar4
  • Prasad, M S N4
  • Gopinath, K S5
  • Rao, Raman N5
  • Violette, Shelia M6
  • And 2 more
  • 1 Division of Molecular Medicine, St. John's Research Institute, Bangalore, India. , (India)
  • 2 Kidwai Medical Institute of Oncology, Bangalore, India. , (India)
  • 3 St. John's Medical College and Hospital, Bangalore, India. , (India)
  • 4 Shankara Cancer Hospital and Research Centre, Bangalore, India. , (India)
  • 5 Rangadore Memorial Hospital, Bangalore, India. , (India)
  • 6 Biogen Inc., Cambridge, MA.
Type
Published Article
Journal
Cancer Medicine
Publisher
Wiley
Publication Date
Aug 01, 2016
Volume
5
Issue
8
Pages
2000–2011
Identifiers
DOI: 10.1002/cam4.756
PMID: 27184932
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho-Rac pathway including downstream genes (ACTR2, ACTR3) and effector proteinases (MMP9, MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2- and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho-Rac pathway (P-values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease-free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9-8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node-positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho-Rac pathway through increased expression of MMP9 and MMP15. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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