Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer

Version 1 : Received: 24 December 2022 / Approved: 3 January 2023 / Online: 3 January 2023 (06:57:38 CET)

A peer-reviewed article of this Preprint also exists.

Purazo, M.L.; Ice, R.J.; Shimpi, R.; Hoenerhoff, M.; Pugacheva, E.N. NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer. Cancers 2023, 15, 1119. Purazo, M.L.; Ice, R.J.; Shimpi, R.; Hoenerhoff, M.; Pugacheva, E.N. NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer. Cancers 2023, 15, 1119.

Abstract

The HER2 overexpression occurs in 10–20% of breast cancer patients. HER2+ tumors are characterized by increase in Ki67, early relapse and increased metastasis. There is little known about factors influencing early stages of HER2- tumorigenesis and diagnostic markers. Previously, it was shown that deletion of NEDD9 in mouse models of HER2 cancer interferes with tumor growth, but the role of NEDD9 upregulation is currently unexplored. We report that NEDD9 is overexpressed in a significant subset of HER2+ breast cancers and correlates with limited response to anti-HER2 therapy. To investigate the mechanisms through which NEDD9 influences HER2-dependent tumorigenesis, we generated MMTV-Cre-NEDD9 transgenic mice. The analysis of mammary glands shows extensive ductal epithelium hyperplasia, increased branching, and terminal end bud expansion. The addition of oncogene Erbb2 (neu) leads to development of early hyperplastic benign lesions earlier (~16 weeks) with a significantly shorter latency than the control mice. Similarly, NEDD9 upregulation in MCF10A-derived acini leads to hyperplasia like DCIS. This phenotype is associated with activation of ERK1/2 and AURKA kinases leading to an increased proliferation of luminal cells. These findings indicate that NEDD9 is setting permissive conditions for HER2-induced tumorigenesis, thus identifying this protein as a potential diagnostic marker for early detection.

Keywords

HER2; breast cancer; NEDD9 adaptor protein; hyperplasia; AURKA

Subject

Medicine and Pharmacology, Oncology and Oncogenics

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