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Sources of Funding: None

Introduction

A significant amount of patients with non-muscle-invasive bladder cancer (BC) fail to respond to intravesical BCG immunotherapy. Interestingly, in a few studies, male patients have been shown to be less likely to respond to BCG therapy, compared with female patients. Meanwhile, emerging preclinical evidence suggests the involvement of androgen receptor (AR) signaling in urothelial tumorigenesis and cancer progression. This study aims to assess whether AR signals have an impact on the direct cytotoxic effects of BCG on BC cell growth.

Methods

We compared the inhibitory effects of BCG on BC cell viability, colony formation, or cell migration, between AR-positive (e.g. UMUC3, 5637/647V stably expressing wild-type AR) versus AR-negative lines (e.g. UMUC3 stably expressing AR-shRNA, 5637/647V) or between AR-positive lines with versus without treatment with a synthetic androgen methytrienolone (R1881) and/or an anti-androgen hydroxyflutamide (HF). We also determined the expression of AR and PTEN (whose knockdown in BC cells has correlated with increased BCG uptake) in these AR-positive/negative lines as well as in "BCG-resistant" UMUC3/5637-AR/647V-AR sublines established following long-term culture with low-doses of BCG, using western blot. Immunohistochemistry (IHC) of AR was then performed in tissue microarrays consisting of BCs from patients who subsequently underwent BCG therapy.

Results

BCG treatment reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in an androgen-depleted condition and in the presence of androgens, R1881 and HF treatments lowered and enhanced the BCG effects, respectively. In addition, BCG more significantly inhibited cell migration of AR-negative lines or AR-positive lines with mock treatment, compared to AR-positive lines without or with R1881 treatment, respectively. Furthermore, the expression levels of AR and PTEN were considerably elevated in R1881-treated AR-positive lines as well as BCG-resistant sublines, compared to respective controls. Finally, IHC showed AR positivity in 2 (14%) of 14 responders versus 8 (57%) of 14 non-responders (P=0.046), and the difference was even more significant in male patients [2/13 (15%) vs. 7/11 (64%); P=0.033].

Conclusions

These findings suggest that AR activity correlates with resistance to BCG treatment in BC cells. Accordingly, anti-androgenic drugs may function as sensitizers of BCG therapy especially in male patients with AR-positive BC.

Funding

None