ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

PURPOSE: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. EXPERIMENTAL DESIGN: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. RESULTS: We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. CONCLUSIONS: In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion.

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions.

Baicalein Is a Phytohormone that Signals Through the Progesterone and Glucocorticoid Receptors.

While flavonoids have been studied extensively for estrogen receptor activity, they have not been well studied for their ability to modify progesterone receptor (PR) and glucocorticoid receptor (GR) signaling. Three flavonoid compounds, tangeretin, wogonin, and baicalein, were selected for testing for PR and GR activity based on their structural similarity to known phytoprogesterone-like compounds. Each compound was docked in the binding pocket of PR and GR. Of these compounds, baicalein was predicted to be most likely to bind to both receptors. A fluorescence polarization competitive binding assay for PR and GR confirmed that baicalein binds to both the PR and GR with IC50 values of 15.30 µM and 19.26 µM, respectively. In Ishikawa PR-B and T47D cells, baicalein acted as a PR antagonist in a hormone response element (HRE) luciferase (Luc) assay. In OVCAR5 cells, which only express GR, baicalein was a GR agonist via an HRE/Luc assay and induced GR target genes, FKBP5 and GILZ. RU486, a PR and GR antagonist, abrogated baicalein's activity in OVCAR5 cells, confirming baicalein's activity is mediated through the GR. In vivo, baicalein administered intraperitoneally to female mice twice a week for 4 weeks at a dose of 25 mg/kg induced the GR target gene GILZ in the reproductive tract, which was blocked by RU486. In summary, baicalein has PR antagonist and GR agonist activity in vitro and demonstrates GR agonist activity in the uterus in vivo.