IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma
Sha Zhu, B. Marie Ward, Jun Yu, Asia N. Matthew-Onabanjo, Jenny Janusis, Chung-Cheng Hsieh, Keith Tomaszewicz, Lloyd Hutchinson, Lihua Julie Zhu, Dina Kandil, Leslie M. Shaw
Sha Zhu, B. Marie Ward, Jun Yu, Asia N. Matthew-Onabanjo, Jenny Janusis, Chung-Cheng Hsieh, Keith Tomaszewicz, Lloyd Hutchinson, Lihua Julie Zhu, Dina Kandil, Leslie M. Shaw
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Research Article Oncology

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma

Abstract

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.

Authors

Sha Zhu, B. Marie Ward, Jun Yu, Asia N. Matthew-Onabanjo, Jenny Janusis, Chung-Cheng Hsieh, Keith Tomaszewicz, Lloyd Hutchinson, Lihua Julie Zhu, Dina Kandil, Leslie M. Shaw

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Figure 4

IRS2 mutations linked to invasion.

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IRS2 mutations linked to invasion. (A) Immunoblots of cell extracts fro...
(A) Immunoblots of cell extracts from SUM-159 parental cells and SUM-159:IRS1–/–,IRS2–/– cells stably expressing empty vector (pCDH), wild-type (WT) human insulin receptor substrate 2 (IRS2), or the IRS2 mutants identified in pleomorphic invasive lobular carcinoma (PILC). (B) Representative images used to score invasive colonies grown in Matrigel/collagen I gels. Cells grown in a Matrigel/collagen I gel were scored for (C) the extent of invasion (mean ± SD, n = 20 wells from 5 independent experiments) or (D) the distance of invasive branching (mean ± SD, n = 50 colonies from 1 of 3 representative experiments). Representative images for each cell line are shown. (E) Cell migration assay using Transwell culture chambers (mean ± SD of 4 independent experiments). (F) Glucose uptake assay (mean ± SD of 4 independent experiments). (G) Immunoblots of cell extracts from PyMT:Irs1–/–,Irs2–/– cells stably expressing empty vector (pcDNA), wild-type human IRS2 (WT), or the IRS2 mutants identified in PILC. Cells grown in a Matrigel/collagen I gel were scored for (H) the extent of invasion (mean ± SD, n = 12 wells from 5 independent experiments) or (I) the distance of invasive branching (mean ± SD, n = 50 colonies from 1 of 3 representative experiments). Representative images for each cell line are shown. Student’s t test was performed between vector (pCDH or pcDNA) and WT-IRS2, and 1-way ANOVA with Bonferroni post hoc testing was performed between WT-IRS2 and IRS2 mutants. *P < 0.05, relative to pCDH; ***P < 0.001, relative to pcDNA; #P < 0.05, ##P < 0.01, ###P < 0.001, relative to WT-IRS2. Scale bar: 20 μm.