Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

Hua Wang; Dongxi Xiang; Ben Liu; Aina He; Helena J Randle; Kelvin Xi Zhang; Anushka Dongre; Norman Sachs; Allison P Clark; Luwei Tao; Qing Chen; Vladimir V Botchkarev; Ying Xie; Ning Dai; Hans Clevers; Zhe Li; David M Livingston

doi:10.1016/j.cell.2019.06.002

Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

Hua Wang, Dongxi Xiang, Ben Liu, Aina He, Helena J Randle, Kelvin Xi Zhang, Anushka Dongre, Norman Sachs, Allison P Clark, Luwei Tao, Qing Chen, Vladimir V Botchkarev, Ying Xie, Ning Dai, Hans Clevers, Zhe Li, David M Livingston

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

56 Citations (Scopus)

Abstract

Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Original language	English
Pages (from-to)	135-151.e19
Journal	Cell
Volume	178
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.06.002
Publication status	Published - 27 Jun 2019

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Wang, H., Xiang, D., Liu, B., He, A., Randle, H. J., Zhang, K. X., Dongre, A., Sachs, N., Clark, A. P., Tao, L., Chen, Q., Botchkarev, V. V., Xie, Y., Dai, N., Clevers, H., Li, Z., & Livingston, D. M. (2019). Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer. Cell, 178(1), 135-151.e19. https://doi.org/10.1016/j.cell.2019.06.002

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title = "Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer",

abstract = "Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.",

author = "Hua Wang and Dongxi Xiang and Ben Liu and Aina He and Randle, {Helena J} and Zhang, {Kelvin Xi} and Anushka Dongre and Norman Sachs and Clark, {Allison P} and Luwei Tao and Qing Chen and Botchkarev, {Vladimir V} and Ying Xie and Ning Dai and Hans Clevers and Zhe Li and Livingston, {David M}",

year = "2019",

month = jun,

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doi = "10.1016/j.cell.2019.06.002",

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T1 - Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

AU - Wang, Hua

AU - Xiang, Dongxi

AU - Liu, Ben

AU - He, Aina

AU - Randle, Helena J

AU - Zhang, Kelvin Xi

AU - Dongre, Anushka

AU - Sachs, Norman

AU - Clark, Allison P

AU - Tao, Luwei

AU - Chen, Qing

AU - Botchkarev, Vladimir V

AU - Xie, Ying

AU - Dai, Ning

AU - Clevers, Hans

AU - Li, Zhe

AU - Livingston, David M

PY - 2019/6/27

Y1 - 2019/6/27

N2 - Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

AB - Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

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DO - 10.1016/j.cell.2019.06.002

M3 - Article

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SN - 0092-8674

VL - 178

SP - 135-151.e19

JO - Cell

JF - Cell

IS - 1

ER -

Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

Abstract

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