Fig. 4: Mechanisms contributing to reduced chemosensitivity in dioestrus.

a, Percentage of mesenchymal tumour cells determined in treatment-naive tumours of genetic MMTV-PyMT model at different oestrous cycle stages; n = 3 mice/24 tumours per group. b, Left, imunohistochemical staining for CD31; right, quantified diameter of intratumoural vasculature in treatment-naive genetic MMTV-PyMT tumours during stages of oestrous cycle. n = 3 mice/12 tumours per oestrous stage. c, Left, immunohistochemical staining for F4/80 (left). Quantification of percentage of F4/80⁺ cells in treatment-naive tumours (middle) or 7 days post treatment (right) in the genetic MMTV-PyMT model at oestrus and dioestrus. n: O^pre = 5 mice/21 tumours; D^pre = 7 mice/27 tumours; O^post = 3 mice/12 tumours; D^post = 3 mice/11 tumours. d, Schematic representation of experimental set-up. e, Immunohistochemical staining of chemotherapy treatment-naive tumours treated with either control antibody (anti-IgG2a) (top, representative of 15 tumours/3 mice) or macrophage depletion antibody (Ab) (anti-CSF1R) (bottom, representative of 21 tumours/5 mice). f,g, Percentage of PI⁺ tumour cells (f) and tumour volume change compared with baseline (g) for mice receiving control antibody (anti-IgG2a) or macrophage depletion antibody (anti-CSF1R) and treatment with doxorubicin. n: O^a-IgG2a = 6 mice/24 tumours; D^a-IgG2a = 6 mice/28 tumours; O^a-CSF1R = 4 mice/17 tumours; D^a-CSF1R = 5 mice/21 tumours. a,b,c,f,g, Thicker solid lines represent median, and thinner solid lines the 25th and 75th percentiles. Dots represent either individual tumours (a–c,f) or mice (g). Statistical analysis was performed using a linear mixed-effects model (a,c) or a two-sided (b) or one-sided (f,g) Wilcoxon–Mann–Whitney test. *P < 0.05, **P < 0.01, ***P < 0.001. Further details on statistical analysis are provided in Supplementary File 1. Scale bars, 500 µm (b (left)), 50 µm (b (right), c (right)), 200 µm (c (left), e).

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