Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer

Abstract

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R 2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9–3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22–1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors.

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

“…These data suggest that CPNE1‐high‐expressing TNBC cells are resistant to DNA‐damaging radiotherapy. Consistent with our results, other studies reported that MDA‐MB‐231 cells demonstrated a higher survival fraction than MDA‐MB‐468 cells after 2 or 4 Gy 28,29 . However, the differences in colony formation between MDA‐MB‐468 and MDA‐MB‐231 cells after 4 Gy were not significant 30 .…”

“…MDA-MB-468 cells after 2 or 4 Gy. 28,29 However, the differences in colony formation between MDA-MB-468 and MDA-MB-231 cells after 4 Gy were not significant. 30 It was recently reported that PI3K/ AKT inhibitor inhibited the resistance to endocrine or DNA-damaging radiotherapy in ER-positive early patients with BC.…”

DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress in triplenegative breast cancer

“…These results establish DYRK2 protein levels as potential prognostic factor and promissing novel therapeutic target in TNBC, especially in the TN/AR-negative subgroup of patients, for whom there is no targeted therapy available. Interestingly, several of the commonly used TNBC cell models (including the two cell lines used in this study, MDA-MB-231 and MDA-MB-468) are also AR negative 23 , and thus there is full agreement between our cell culture and tissue analysis data.…”

Seviteronel, a Novel CYP17 Lyase Inhibitor and Androgen Receptor Antagonist, Radiosensitizes AR-Positive Triple Negative Breast Cancer Cells

“…Beyond the role of the androgen receptor in driving cancer cell proliferation, previous work in prostate cancer and breast cancer has demonstrated the role of AR in mediating DNA repair and in the DNA damage response following radiation therapy (26)(27)(28)(29). These studies suggest that pharmacologic abrogation of AR both in prostate cancer (darolutamide and enzalutamide) and in AR+ TNBC (enzalutamide) may be a viable treatment strategy for the radiosensitization of aggressive tumors, as AR inhibition may inhibit DNA repair.…”

“…These studies suggest that pharmacologic abrogation of AR both in prostate cancer (darolutamide and enzalutamide) and in AR+ TNBC (enzalutamide) may be a viable treatment strategy for the radiosensitization of aggressive tumors, as AR inhibition may inhibit DNA repair. In addition, following radiation, AR activity increases the expression and phosphorylation of DNAPKcs (26,28). Therefore, AR inhibition may render cells more sensitive to radiation treatment by reducing activity of DNAPKcs and inhibiting non-homologous end joining (NHEJ), but not homologous recombination (HR) (27).…”