R-spondin-3 promotes proliferation and invasion of breast cancer cells independently of Wnt signaling

We recently identified R-spondin-3 (RSPO3) as a novel driver of breast cancer associating with reduced patient survival, expanding its clinical value as potential therapeutic target that had been recognized mostly for colorectal cancer so far. (Pre)clinical studies exploring RSPO3 targeting in colorectal cancer approach this indirectly with Wnt inhibitors, or directly with anti-RSPO3 antibodies. Here, we address the clinical relevance of RSPO3 in breast cancer and provide insight in the oncogenic activities of RSPO3. Utilizing the RSPO3 breast cancer mouse model, we show that RSPO3 drives the aberrant expansion of luminal progenitor cells expressing cancer stem cell marker CD61, inducing proliferative, poorly differentiated and invasive tumors. Complementary studies with tumor organoids and human breast cancer cell lines demonstrate that RSPO3 consistently promotes the proliferation and invasion of breast cancer cells. Importantly, RSPO3 exerts these oncogenic effects independently of Wnt signaling, rejecting the therapeutic value of Wnt inhibitors in RSPO3-driven breast cancer. Instead, direct RSPO3 targeting effectively inhibited RSPO3-driven growth of breast cancer cells. Conclusively, our data indicate that RSPO3 exerts unfavorable oncogenic effects in breast cancer, enhancing proliferation and malignancy in a Wnt-independent fashion, proposing RSPO3 itself as a valuable therapeutic target in breast cancer.