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01-12-2018 | Preclinical study

CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast

Authors: Emily R. McMullen, Maria E. Gonzalez, Stephanie L. Skala, Mai Tran, Dafydd Thomas, Sabra I. Djomehri, Boris Burman, Kelley M. Kidwell, Celina G. Kleer

Published in: Breast Cancer Research and Treatment | Issue 3/2018

Abstract

Purpose

Metaplastic breast carcinomas are an aggressive subtype of triple-negative breast cancer (TNBC) in which part or all of the adenocarcinoma transforms into a non-glandular component (e.g., spindled, squamous, or heterologous). We discovered that mammary-specific Ccn6/Wisp3 knockout mice develop mammary carcinomas with spindle and squamous differentiation that share upregulation of the oncofetal proteins IGF2BP2 (IMP2) and HMGA2 with human metaplastic carcinomas. Here, we investigated the functional relationship between CCN6, IGF2BP2, and HMGA2 proteins in vitro and in vivo, and their expression in human tissue samples.

Methods

MMTV-cre;Ccn6^fl/fl tumors and spindle TNBC cell lines were treated with recombinant CCN6 protein or vehicle. IGF2BP2 was downregulated using shRNAs in HME cells with stable CCN6 shRNA knockdown, and subjected to invasion and adhesion assays. Thirty-one human metaplastic carcinomas were arrayed in a tissue microarray (TMA) and immunostained for CCN6, IGF2BP2, and HMGA2.

Results

CCN6 regulates IGF2BP2 and HMGA2 protein expression in MMTV-cre;Ccn6^fl/fl tumors, in MDA-MB-231 and − 468, and in HME cells. CCN6 recombinant protein reduced IGF2BP2 and HMGA2 protein expression, and decreased growth of MMTV-cre;Ccn6^fl/fl tumors in vivo. IGF2BP2 shRNA knockdown was sufficient to reverse the invasive abilities conferred by CCN6 knockdown in HME cells. Analyses of the TCGA Breast Cancer Cohort (n = 1238) showed that IGF2BP2 and HMGA2 are significantly upregulated in metaplastic carcinoma compared to other breast cancer subtypes. In clinical samples, low CCN6 is frequent in tumors with high IGF2BP2/HMGA2 with spindle and squamous differentiation.

Conclusions

These data shed light into the pathogenesis of metaplastic carcinoma and demonstrate a novel CCN6/IGF2BP2/HMGA2 oncogenic pathway with biomarker and therapeutic implications.

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Title: CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast
Authors: Emily R. McMullen
Maria E. Gonzalez
Stephanie L. Skala
Mai Tran
Dafydd Thomas
Sabra I. Djomehri
Boris Burman
Kelley M. Kidwell
Celina G. Kleer
Publication date: 01-12-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4960-2

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Abstract

Purpose

Methods

Results

Conclusions

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