WFDC3 inhibits tumor metastasis by promoting the ERβ-mediated transcriptional repression of TGFBR1 in colorectal cancer

Abstract

Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERβ/TGFBR1 signaling axis. WFDC3 interacts with ERβ and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERβ-mediated transcription. Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients.

Survival outcome and prognostic factors for early-onset and late-onset metastatic colorectal cancer: a population based study from SEER database

“…Notably, women experience menopause around the age of 50, which coincides with this age-related difference. Estrogen, a crucial sex hormone 48,49 , exerts various biological effects and has been shown in previous studies to inhibit colorectal cancer by altering the ratio of ERα to ERβ 50 . Additionally, estrogen may exert a protective role by influencing MSI status and gene methylation 51 .…”

Role of gonadally synthesized steroid hormones in the colorectal cancer microenvironment

“…The tumor suppressor protein known as WFDC3 plays a crucial role in inhibiting the spread of tumors in colorectal cancer. This inhibition is achieved through the promotion of ERβ-mediated transcriptional repression of TGFBR1 ( 53 ).…”

PFDN6 contributes to colorectal cancer progression via transcriptional regulation

“…1 The survival rate of patients with metastatic CRC has been documented to be below 10% within a 5-year time frame. 2 Projections indicate an anticipated surge of 2.2 million fresh CRC cases and 1.1 million fatalities by the year 2030, signifying a notable 60% escalation in the global burden. 3 4 Surgical intervention, radiotherapy, chemotherapy and targeted therapy are viable modalities for managing CRC.…”