Abstract 1448: Investigating the effects of estrogen on the initiation of prostate cancer
Authors: Denic Nash S. , Swift-Gallant Ashlyn , Kao Kenneth R. 
Published: March 2024

Background: Prostate cancer (PCa) is responsible for ~10% of cancer-related deaths in men. Nkx3.1 is an androgen-regulated gene expressed primarily in the prostate, which encodes a tumor suppressor protein important for male reproductive development. Loss of nkx3.1 is thought to lead to prostatic intraepithelial neoplasia (PIN), the pre-invasive form of prostatic adenocarcinoma. Previous evidence suggests that estrogenic dysregulation and testosterone imbalance play a significant role in PCa initiation and progression.

Objectives/Aims: We aimed to investigate how estrogen impacts the progression of PIN in the anterior prostate of mice lacking nkx3.1.

Methods: To investigate the effect of long-term exposure to 17β-estradiol (E2), nkx3.1+/+ and nkx3.1−/− 12-week-old mice were given 2 mg/day of E2 over 90 days by subdermal implantation of 90-day extended-release tablets. After 90 days, the anterior prostate lobes of the mice were harvested and analyzed post-treatment for signs of pre-cancerous tissue. The immediate, early effect of E2 exposure was also investigated by the subcutaneous injection of 8- and 20-week-old mice with 0.300 mg/kg of E2. Within two hours, the anterior prostate lobes were harvested, and ~500 ng/μL of RNA was isolated from the tissues. cDNA was reverse-transcribed, in triplicate, from the RNA and the expression of c-myc, p53, estrogen receptor ERα (ESR1), and ERβ (ESR2) were assessed via qRT-PCR. Three technical replicates from three biological replicates were performed for each treatment.

Results: Nkx3.1−/− mice chronically exposed to elevated E2 developed PIN following E2 treatment, while the placebo group had tissue hyperplasia. Nkx3.1+/+ mice had normal prostate tissue regardless of E2 treatment. In response to immediate exposure to E2, the prostates of 8-week-old nkx3.1+/+ mice showed reduced c-myc expression. 8-week-old nkx3.1−/− mice showed no changes in expression of any of the four genes assayed, in response to E2 as compared to the placebo treatment. In contrast, regardless of exposure to E2, c-myc, p53, and ESR2 were significantly elevated in these mice compared to the nkx3.1+/+ groups. Furthermore, c-myc and p53 expression was suppressed in 20-week-old nkx3.1−/− mice in response to E2, while ESR1 and ESR2 remained unchanged.

Conclusion: Our evidence suggested that prolonged exposure of wild-type mice to E2 had no pathohistological impact on the anterior prostate tissue. In nkx3.1-deficient mice, however, E2 exposure promoted the onset of PIN, and caused immediate differential expression of estrogen-responsive genes, suggesting a role of nkx3.1 in protecting the prostate in the presence of a hormonal imbalance.

Citation Format: Nash S. Denic, Ashlyn Swift-Gallant, Kenneth R. Kao. Investigating the effects of estrogen on the initiation of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1448.