TY - JOUR
T1 - Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer
AU - Su, Ying
AU - Subedee, Ashim
AU - Bloushtain-Qimron, Noga
AU - Savova, Virginia
AU - Krzystanek, Marcin
AU - Li, Lewyn
AU - Marusyk, Andriy
AU - Tabassum, Doris P.
AU - Zak, Alexander
AU - Flacker, Mary Jo
AU - Li, Mei
AU - Lin, Jessica J.
AU - Sukumar, Saraswati
AU - Suzuki, Hiromu
AU - Long, Henry
AU - Szallasi, Zoltan
AU - Gimelbrant, Alexander
AU - Maruyama, Reo
AU - Polyak, Kornelia
N1 - Funding Information:
We thank members of our laboratories for their critical reading of this manuscript and useful discussions and the Cytogenetics Core of Dana-Farber Harvard Cancer Center (P30 CA006516) for the SKY studies. This work was supported by the US Army Congressionally Directed Research Program BC084006 and BC134001 (K.P.) and BC087579 (A.M.), Kræftens Bekæmpelse, the Danish Cancer Society (M.K.), and the Susan G. Komen Foundation (R.M. and Y.S.).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/6/16
Y1 - 2015/6/16
N2 - Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Luminal and basal-like breast tumors are clinically distinct. Using somatic cell fusions, Su et al. demonstrate the general dominance of the basal-like phenotype. Epigenomic profiling of parental luminal and basal-like cells and heterofusions define common luminal programs but a high degree of heterogeneity in basal-like cancer cells.
AB - Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Luminal and basal-like breast tumors are clinically distinct. Using somatic cell fusions, Su et al. demonstrate the general dominance of the basal-like phenotype. Epigenomic profiling of parental luminal and basal-like cells and heterofusions define common luminal programs but a high degree of heterogeneity in basal-like cancer cells.
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U2 - 10.1016/j.celrep.2015.05.011
DO - 10.1016/j.celrep.2015.05.011
M3 - Article
C2 - 26051943
AN - SCOPUS:84937643828
SN - 2211-1247
VL - 11
SP - 1549
EP - 1563
JO - Cell Reports
JF - Cell Reports
IS - 10
ER -