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. 2022 May 12;13:2642. doi: 10.1038/s41467-022-30375-8

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 9 — a Two CDK12^HIGH (Pt#1 and #2) and two CDK12^LOW (Pt#3 and #4) breast cancer patient-derived xenografts (PDXs) were silenced with a lentiviral CDK12 shRNA or with a control shRNA (Ctr), and injected orthotopically into the mammary fat pads of NGS mice. Tumor volume was measured at the endpoint (4–6 weeks post-injection). Bars represent the mean ± SD (6 mice per experimental group). ***P < 0.001 vs. Ctr-KD cells, two-sided unpaired t-test. b Kaplan–Meier survival analysis of mice injected intracardiacally with CDK12^HIGH Pt#1 and Pt#2, or CDK12^LOW Pt#3 PDX cells treated as in (a). Individual mice were sacrificed when signs of distress or severe debilitation became manifest. Number of mice/experimental group: PT#1, 14 for Ctr-KD and 13 for CDK12-KD; Pt#2, 23 for Ctr-KD and 12 for CDK12-KD; Pt#3, 14 for Ctr-KD and 14 for CDK12-KD. P, P-values, by log-rank test. c RT-qPCR analysis of the indicated SGOC genes in CDK12^HIGH PDX cells (Pt#1 and Pt#2) silenced or not for CDK12 as in (a). Data are expressed as relative to control shRNA (Ctr-KD = 1) for each condition. Bars represent the means ± SEM (n = 5, Pt#1; n = 3, Pt#2). *P < 0.05; **P < 0.01; ***P < 0.001, vs. Ctr-KD, two-sided unpaired t-test. d Relative abundance of the indicated folate cycle metabolites in CDK12^HIGH PDX-derived cells control- (Ctr-KD) or CDK12-silenced (CDK12-KD), identified by LC-MS metabolomics. Data are expressed as relative to an internal standard (reserpine) and are means ± SD (n = 3). **P = 0.001; ***P < 0.001, vs. Ctr-KD, two-sided unpaired t-test. e Three-day in vitro proliferation of CDK12^HIGH (Pt #1 and #2) vs. CDK12^LOW (Pt #3) cells, control silenced (Ctr-KD) or silenced for CDK12 (CDK12-KD), PSAT1 (PSAT1-KD) and MTHFD1 (MTHFD1-KD), or cultured in the presence of THZ531 (100 nM). Data are expressed as relative to day 3 in each condition and are the mean ± SD (n = 3). ***P < 0.001 relative to Ctr-KD in each condition, two-sided unpaired t-test. Source data are provided as Source Data file.