PtdIns(3,4,5)P₃-dependent Rac exchanger 1 (P-Rex1) promotes mammary tumor initiation and metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• P-Rex1 (Phosphatase of regenerating kinase 1) is a Rac-guanine nucleotide exchange factor (GEF) activating Rac1 signaling.
• P-Rex1's role in breast cancer is complex, with varied impacts on disease progression and outcome.
• Previous studies suggest P-Rex1 promotes melanoma progression.

Purpose of the Study:

• To investigate the role of P-Rex1 in breast cancer initiation, progression, and metastasis.
• To clarify the association between P-Rex1 expression and breast cancer patient outcomes.
• To explore therapeutic strategies targeting P-Rex1/Rac1 signaling.

Main Methods:

• Analysis of human breast cancer databases (METABRIC cohort) and gene array expression data.
• Generation of murine models with P-Rex1 gain or loss of function (MMTV-driven transgenics, MMTV-neu, MMTV-PyMT).
• In vivo and in vitro assays assessing Rac1 activation, cell proliferation, tumor formation, invasion, and metastasis; pharmacological inhibition of Rac1/MEK1/2.

Main Results:

• Higher P-Rex1 mRNA levels correlated with poor outcome in ER-positive/luminal B breast cancers.
• P-Rex1 deletion in mice improved survival and reduced Rac1 activation.
• Overexpression of P-Rex1 in mice led to polarity defects, hyperplasia, mammary tumor development, increased tumor initiation, and enhanced metastasis, but did not affect primary tumor growth.
• Inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and invasion.

Conclusions:

• P-Rex1 functions as an oncogene in breast cancer, cooperating with HER2/neu to promote tumor initiation and metastasis.
• P-Rex1 expression is a prognostic marker for poor outcome in luminal B breast cancers.
• Targeting P-Rex1 or its downstream effectors (Rac1, MEK1/2) may represent a therapeutic strategy for breast cancer.