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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 (R2 = 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.
Highlights
Radiation therapy (RT), in addition to surgery and systemic therapy, remains a mainstay of current clinical management of breast cancer
As activation of DNA protein kinase catalytic subunit (DNAPKcs) is known to be an immediate event after ionizing radiation, we found that androgen receptor (AR) + triple-negative breast cancer (TNBC) cell lines treated with MDV3100 had a significant decrease in pDNAPKcs levels at multiple time points within the first 30 min after radiation (Fig. 6b), suggesting AR function was necessary for early activation of DNAPKcs and double stranded DNA (dsDNA) break repair
RNA and protein expression profiling of over 2000 human breast tumors demonstrates that AR RNA and protein expression is strongly correlated across all subtypes of breast cancer, and that significant heterogeneity exists amongst all subtypes for AR expression, suggesting potential benefit outside of TNBC
Summary
Radiation therapy (RT), in addition to surgery and systemic therapy, remains a mainstay of current clinical management of breast cancer. Effective in most women, some will develop recurrent disease despite multi-modality therapy, including a significant percentage of the ~42,000 women diagnosed with triple-negative breast cancer (TNBC) each year.[1] Studies detailing the poor response of TNBC to adjuvant RT underscore the biologic differences and as yet undefined oncogenic drivers of these particular types of tumors, with TNBC much less likely to have significant local- and disease-free survival advantages from adjuvant RT and chemotherapy treatment in women.[2,3,4] Given the lack of targeted agents for TNBC and their relative RT insensitivity (as evidenced by their increased locoregional recurrence risk) the development of additional targets for radiosensitization represents a critical unmet clinical need. Multiple clinical trials are assessing the effect of androgen receptor blockade in patients with metastatic breast cancer whose tumors express AR (NCT03055312, NCT01889238, NCT02580448, NCT01889238, NCT00468715, NCT00755885- clinicaltrials.gov)
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