Abstract
Mammary epithelia are composed of luminal and myoepithelial/basal cells whose neoplastic transformations lead to distinct types of breast cancers with diverse clinical features. We report that mice deficient for the CDK4/6 inhibitor p18(Ink4c) spontaneously develop ER-positive luminal tumors at a high penetrance. Ink4c deletion stimulates luminal progenitor cell proliferation at pubertal age and maintains an expanded luminal progenitor cell population throughout life. We demonstrate that GATA3 binds to and represses INK4C transcription. In human breast cancers, low INK4C and high GATA3 expressions are simultaneously observed in luminal A type tumors and predict a favorable patient outcome. Hence, p18(INK4C) is a downstream target of GATA3, constrains luminal progenitor cell expansion, and suppresses luminal tumorigenesis in the mammary gland.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology*
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Cell Differentiation
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Cell Transformation, Neoplastic*
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase Inhibitor p18 / genetics
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Cyclin-Dependent Kinase Inhibitor p18 / metabolism*
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Female
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Mammary Glands, Human / metabolism
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Mammary Glands, Human / pathology
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Mice
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Mice, Inbred BALB C
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Stem Cells / metabolism
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Stem Cells / pathology
Substances
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Cyclin-Dependent Kinase Inhibitor p18
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GATA3 Transcription Factor
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GATA3 protein, human
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Gata3 protein, mouse
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CDK4 protein, human
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Cyclin-Dependent Kinase 4