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Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression.

ABSTRACT: A defective homologous recombination (HR) repair program increases tumor incidence as well as providing a survival advantage in patients with breast and ovarian cancers. Here we hypothesize that the tumor-promoting side of genome maintenance programs may be contributed by a self-renewal protein, nucleostemin (NS). To address this issue, we established its functional importance in mammary tumor progression in mice and showed that mammary tumor cells become highly susceptible to replicative DNA damage following NS depletion and are protected from hydroxyurea-induced damage by NS overexpression. Breast cancer cells with basal-like characters display more reliance on NS for genome maintenance than those with luminal characters. Mechanistically, NS-deficient cells demonstrate a significantly reduced HR repair activity. TCGA analyses of human breast cancers revealed that NS is co-enriched positively with HR repair proteins and that high NS expression correlates with low HR defects and predicts poor progression-free survival and resistance to knockdown of cell-cycle checkpoint genes in triple-negative/basal-like breast cancers. This work indicates that NS constitutes a tumor-promoting genome maintenance program required for mammary tumor progression.

SUBMITTER: Lin T

PROVIDER: S-EPMC6525051 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression.

Lin Tao T Lin Tsung-Chin TC McGrail Daniel J DJ Bhupal Parnit K PK Ku Yi-Hsuan YH Zhang Wen W Meng Lingjun L Lin Shiaw-Yih SY Peng Guang G Tsai Robert Y L RYL

Oncogene 20190128 20

A defective homologous recombination (HR) repair program increases tumor incidence as well as providing a survival advantage in patients with breast and ovarian cancers. Here we hypothesize that the tumor-promoting side of genome maintenance programs may be contributed by a self-renewal protein, nucleostemin (NS). To address this issue, we established its functional importance in mammary tumor progression in mice and showed that mammary tumor cells become highly susceptible to replicative DNA da ...[more]

PMID: 30692636

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Project description:Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood.To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen.Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells.This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

Dataset Information

Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression.

Publications

Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression.

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