@article{2eb4e6dca49c444087fc586421480633,
title = "Stem Cell Determinant SOX9 Promotes Lineage Plasticity and Progression in Basal-like Breast Cancer",
abstract = "Lineage plasticity is important for the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. While BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal, and hybrid phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal reprogramming remain unclear. Here, we show that the transcription factor SOX9 acts as a determinant for estrogen-receptor-negative (ER−) luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical nuclear factor κB (NF-κB) signaling. Inactivation of TP53 and RB via expression of SV40 TAg in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-basal reprogramming in vivo. Furthermore, SOX9 deletion inhibits the progression of ductal carcinoma in situ (DCIS)-like lesions to invasive carcinoma. These data show that ER− LSPC determinant SOX9 acts as a lineage plasticity driver for BLBC progression.",
keywords = "DCIS progression, SOX9, basal-like breast cancer, bipotent cells, lineage plasticity, luminal stem progenitor cells",
author = "Christin, {John R.} and Chunhui Wang and Chung, {Chi Yeh} and Yu Liu and Christopher Dravis and Wei Tang and Oktay, {Maja H.} and Wahl, {Geoffrey M.} and Wenjun Guo",
note = "Funding Information: We thank the Flow Cytometry, Histopathology, Analytical Imaging, and Stem Cell Isolation core facilities of Albert Einstein College of Medicine for technical assistance (supported by Albert Einstein Cancer Center support grant P30 CA013330 , New York State Department of Health NYSTEM program shared facility grant C029154 , and NIH grant 1S10OD019961-01 for the P250 High Capacity Slide Scanner). We thank Nasun Hah at the Salk Next Generation Sequencing Core. This work is supported by grants to W.G. from NYSTEM ( C028109 and C029571 ) and DOD BCRP ( W81XWH1810445 ). Work in the laboratory of G.M.W. was supported, in part, by a Salk Cancer Center core grant ( CA014195 ), the NIH /National Cancer Institute (R35 CA197687), the Susan G. Komen Foundation ( SAC110036 ), and the Breast Cancer Research Foundation ( BCRF ). J.R.C. was supported by the NIH 2T32GM007491-36 Training Program in Cellular and Molecular Biology and Genetics. J.R.C. and Y.L. were supported by NYSTEM training grant C30392GG . W.G. is a V Scholar of the V Foundation for Cancer Research and supported by the Mary Kay Foundation . Funding Information: We thank the Flow Cytometry, Histopathology, Analytical Imaging, and Stem Cell Isolation core facilities of Albert Einstein College of Medicine for technical assistance (supported by Albert Einstein Cancer Center support grant P30 CA013330, New York State Department of Health NYSTEM program shared facility grant C029154, and NIH grant 1S10OD019961-01 for the P250 High Capacity Slide Scanner). We thank Nasun Hah at the Salk Next Generation Sequencing Core. This work is supported by grants to W.G. from NYSTEM (C028109 and C029571) and DOD BCRP (W81XWH1810445). Work in the laboratory of G.M.W. was supported, in part, by a Salk Cancer Center core grant (CA014195), the NIH/National Cancer Institute (R35 CA197687), the Susan G. Komen Foundation (SAC110036), and the Breast Cancer Research Foundation (BCRF). J.R.C. was supported by the NIH 2T32GM007491-36 Training Program in Cellular and Molecular Biology and Genetics. J.R.C. and Y.L. were supported by NYSTEM training grant C30392GG. W.G. is a V Scholar of the V Foundation for Cancer Research and supported by the Mary Kay Foundation. J.R.C. C.W. and W.G. conceived the study; J.R.C. C.W. C.-Y.C. Y.L. C.D. and W.T. performed the experiments and acquired and analyzed data; all authors contributed to data interpretation; J.R.C. and W.G. wrote the manuscript with input from all other authors; and G.M.W. and W.G. provided funding. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jun,
day = "9",
doi = "10.1016/j.celrep.2020.107742",
language = "English (US)",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}
