IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma

JCI Insight. 2018 Apr 19;3(8):e97398. doi: 10.1172/jci.insight.97398.


Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular breast cancer that is associated with poor clinical outcomes. Limited molecular data are available to explain the mechanistic basis for PILC behavior. To address this issue, targeted sequencing was performed to identify molecular alterations that define PILC. This sequencing analysis identified genes that distinguish PILC from classic ILC and invasive ductal carcinoma by the incidence of their genomic changes. In particular, insulin receptor substrate 2 (IRS2) is recurrently mutated in PILC, and pathway analysis reveals a role for the insulin receptor (IR)/insulin-like growth factor-1 receptor (IGF1R)/IRS2 signaling pathway in PILC. IRS2 mutations identified in PILC enhance invasion, revealing a role for this signaling adaptor in the aggressive nature of PILC.

Keywords: Breast cancer; Insulin signaling; Oncology.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Breast Neoplasms / pathology
  • Carcinoma, Lobular / genetics*
  • Carcinoma, Lobular / pathology
  • Exome Sequencing / methods
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins / genetics*
  • Lymph Nodes / pathology
  • Middle Aged
  • Mutation, Missense / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / genetics*


  • IGF1R protein, human
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Receptors, Somatomedin
  • Receptor, IGF Type 1