Journal article

CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

April C Watt, Paloma Cejas, Molly J DeCristo, Otto Metzger-Filho, Enid YN Lam, Xintao Qiu, Haley BrinJones, Nikolas Kesten, Rhiannon Coulson, Alba Font-Tello, Klothilda Lim, Raga Vadhi, Veerle W Daniels, Joan Montero, Len Taing, Clifford A Meyer, Omer Gilan, Charles C Bell, Keegan D Korthauer, Claudia Giambartolomei Show all

NATURE CANCER | SPRINGERNATURE | Published : 2021

Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogeno..

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Grants

Awarded by National Health and Medical Research Council of Australia


Awarded by Susan G. Komen for the Cure


Awarded by NIH/NCI


Awarded by US Department of Defense CDMRP


Awarded by Breast Cancer Research Foundation


Awarded by Ministry of Economy and Competitiveness (Instituto de Salud Carlos III)


Awarded by Chan Zuckerberg Initiative (DAF grant)


Awarded by The V Foundation (TVF)


Awarded by Ramon y Cajal Programme, Ministerio de Economia y Competitividad


Awarded by European Union's Horizon 2020 Research and Innovation Programme (Marie Skodowska-Curie


Funding Acknowledgements

This work is supported by the National Health and Medical Research Council of Australia (Investigator Grant GNT1177357 to S.G.); Susan G. Komen for the Cure (to I.K. and M.B. and CCR18547966 to S.G.); the Breast Cancer Alliance (Young Investigator Grant to S.G.); the Royal Australasian College of Physicians (Research Establishment Fellowship to S.G.); Eli Lilly and Co (to S.G.); the NIH/NCI (P50 CA168504 to S.G., I.K., E.W. and J.J.Z.; R35 CA210057 to J.J.Z.; P50 CA165962-06A1 to J.J.Z.; P01CA080111 to M.B.; R01CA193910 to M.L.F.; R02HG005220 to K.D.K. (PI Rafael A. Irizarry), R01GM083084 to K.D.K. (PI Rafael A. Irizarry), U41HG004059 to K.D.K. (PI Martin T. Morgan)); the US Department of Defense CDMRP (W81XWH-18-1-0491 to J.J.Z.); the Breast Cancer Research Foundation (BCRF-18-179 to J.J.Z. and O.M.-F.), the Ministry of Economy and Competitiveness (Instituto de Salud Carlos III) PI18-01604 to P.C.; the Chan Zuckerberg Initiative (DAF grant 2018-183142 to K.D.K. (PI Rafael A. Irizarry)); Stand Up To Cancer (SU2C) and The V Foundation (TVF) SU2C-TVF Convergence Scholar Awards (D2015-037 to J.M.); Ramon y Cajal Programme, Ministerio de Economia y Competitividad (RYC-2015-18357 to J.M.); Terri Brodeur Breast Cancer Foundation (to V.W.D.); and the European Union's Horizon 2020 Research and Innovation Programme (Marie Skodowska-Curie grant agreement no. 754490 to C.G. and the MINDED project).