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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. 7 — a PyMT/CDK12 vs. PyMT/WT xenograft response to MTX (10 mg/kg) or control vehicle (Veh.) (n ≥ 8 tumors/condition). Data, expressed as relative to day 1 of treatment, are the mean ± SEM. *P = 0.019 (8 days); P = 0.013 (12 days) relative to matching control, two-sided unpaired t-test (Scatter plots and fitting curves in Source data). b Number (left) and total area (middle) of synchronous lung metastases detected at the endpoint in the experiment in (a). Data are the mean ± SD; *P = 0.019; ***P < 0.001, two-sided unpaired t-test, relative to vehicle in each condition, and relative to WT in the same experimental condition for vehicle-treated PyMT-CDK12 mice. *P = 0.019; ***P < 0.001. Left, n = lung sections, WT: Veh. n = 8, MTX n = 6; CDK12: Veh. n = 8, MTX n = 6. Middle, n = lung sections, WT: Veh. n = 14, MTX n = 11; CDK12: Veh. n = 12, MTX n = 13. Right, Histology showing the lung metastatic burden for each condition. Inserts, magnification of typical metastatic lesions in dashed boxed. Bars, 3 mm. c Three-days in vitro growth of PyMT/CDK12 vs. PyMT/WT tumor cells treated with paclitaxel (PTX, 20 nM), or MTX (1 μM) vs. vehicle. Data, expressed as to relative 72 h of treatment of each cell line, are the mean ± SD (n = 3). ***P < 0.001 vs. matching condition, two-sided unpaired t-test. d PyMT/CDK12 vs. PyMT/WT xenograft response to first-line PTX (5 mg/kg) and MTX (10 mg/kg) (n ≥ 8 tumors/condition). Data, expressed as relative to day 1 of treatment, are the mean ± SEM. *P < 0.05; **P < 0.01 relative to matching vehicle-treated controls, two-sided unpaired t-test (Scatter plots and fitting curves in Source data). e Representative IHC images for KI67 in PyMT/CDK12-KI vs. PyMT/WT tumor xenografts. The percentage of KI67-positive cells is indicated. Bars, 150 μm. f Growth response in PTX-resistant PyMT/CDK12 xenografts from (d), randomized to second-line MTX (10 mg/kg) or no treatment (Veh.). Data, expressed as relative to day 1 of treatment (n ≥ 4 tumors/condition), are the mean ± SEM. *P = 0.020; **, P = 0.003 relative to vehicle-treated tumors, two-sided unpaired t-test (Scatter plots and fitting curves in Source data). Source data are provided as Source Data file.