Loss of Limb-Bud-and-Heart (LBH) attenuates mammary hyperplasia and tumor development in MMTV-Wnt1 transgenic mice

WNT/β-catenin signaling plays pivotal roles in mammary development and tumorigenesis; and aberrant activation of this pathway is frequently observed in human breast cancer, correlating with poor outcome. However, the mechanisms underlying WNT-driven mammary tumorigenesis remain incompletely understo...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2019-01, Vol.508 (2), p.536-542
Main Authors: Ashad-Bishop, Kilan, Garikapati, Koteswararao, Lindley, Linsey E., Jorda, Merce, Briegel, Karoline J.
Format: Article
Language:English
Subjects:
Animals
Breast cancer
Carcinogenesis - chemically induced
Cell Cycle Proteins
Female
Hyperplasia - prevention & control
Limb-Bud-and-Heart
Mammary Glands, Animal - pathology
Mammary Neoplasms, Animal - prevention & control
Mammary Tumor Virus, Mouse - genetics
Mammary tumorigenesis
Mice
Mice, Transgenic
Mouse model
Nuclear Proteins - deficiency
WNT/β-catenin signaling
Wnt1 Protein - genetics
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Summary:WNT/β-catenin signaling plays pivotal roles in mammary development and tumorigenesis; and aberrant activation of this pathway is frequently observed in human breast cancer, correlating with poor outcome. However, the mechanisms underlying WNT-driven mammary tumorigenesis remain incompletely understood. Here, we used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop aggressive mammary adenocarcinomas, to examine whether Limb-Bud-and-Heart (LBH) - a WNT/β-catenin target transcription co-factor overexpressed in human triple-negative breast cancers with WNT pathway hyperactivation, contributes to WNT-induced tumorigenesis. We found LBH is specifically overexpressed in basal epithelial tumor cells of MMTV-Wnt1 mammary tumors reminiscent of its basal cell-restricted expression in the normal postnatal mammary gland. To determine the role of LBH in mammary tumorigenesis, we crossed MMTV-Wnt1 mice with basal epithelial-specific Keratin 14/K14-Cre;LbhloxP knockout mice. Mammary glands from virgin LBH-deficient MMTV-Wnt1 mice exhibited reduced hyperplasia, cell proliferation and increased apoptosis. Importantly, LBH inactivation in mammary epithelium significantly delayed tumor onset in MMTV-Wnt1 transgenic mice, with a median tumor-free survival of 32.5 weeks compared to 22.5 weeks in control LBH wild type MMTV-Wnt1 mice (p 
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.11.155