# A Novel LGR4 Oncogenic Signaling in Breast Cancer Progression and Metastasis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $362,569

## Abstract

LGR4, LGR5, and LGR6 comprise a group of proteins in the leucine-rich repeat-containing G-protein-coupled
receptors (LGR). They are known to play important and non-redundant roles in development, stem cells, and
cancer. These functions are generally independent of heterotrimeric G proteins or β-arrestin and have been
attributed to their role in potentiating Wnt signaling. However, we have discovered that LGR4 can also bind and
sequester CBL, a known E3 ligase for pEGFR, independent of RSPO. And we also found that LGR4 can
regulate the level of phosphorylated EGFR independent of RSPO and Wnt signaling. Therefore, our preliminary
data suggest a provocative new signaling pathway by which these LGR proteins regulate human cancer.
Furthermore, we found that LGR4 is most highly expressed in BLBC compared to the other breast cancer
subtypes, and that its knockdown in BLBC breast cancer cell lines inhibits cell migration and invasion in vitro
and metastases in vivo. Therefore, these preliminary data suggest the hypothesis that LGR4 binds CBL and
prevents it from targeting pEGFR for ubiquitin-mediated proteasomal degradation, leading to sustained EGFR
signaling, and that this novel LGR4-CBL-EGFR signaling pathway, together with LGR4-stimulated Wnt
signaling, promotes BLBC invasion and metastasis. Consequently, blockade of both EGFR and canonical Wnt
signaling could prevent or treat metastasis of BLBC, which often has elevated levels of LGR4. To test this
hypothesis and its potential clinical implications, we propose three aims: Aim 1: To elucidate the novel
interaction between LGR4 and CBL in relation to EGFR activation. Aim 2: To establish LGR4 roles in breast
cancer metastasis using mouse models and patient-derived xenografts (PDXs). Aim 3: To determine in mouse
models, PDX, and human clinical samples whether both EGFR and Wnt signaling play critical roles in breast
cancer metastasis stimulated by LGR4, and whether blockade of both EGFR and canonical Wnt signaling
prevents and treats metastases of BLBC more effectively than blockade of either one alone.

## Key facts

- **NIH application ID:** 9851372
- **Project number:** 5R01CA204926-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yi Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,569
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851372

## Citation

> US National Institutes of Health, RePORTER application 9851372, A Novel LGR4 Oncogenic Signaling in Breast Cancer Progression and Metastasis (5R01CA204926-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851372. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*