SIPA1 encodes a GTPase-activating protein that inactivates the Ras-related GTPases Rap1 and Rap2 by promoting GTP hydrolysis 1. Beyond its canonical GAP function, recent evidence suggests SIPA1 also acts as a transcription factor in triple-negative breast cancer, binding DNA and regulating genes involved in cell adhesion and migration 2. SIPA1 expression is tightly regulated during lymphocyte proliferation, induced by mitogenic stimulation and suppressed in transformed cells, suggesting a role in negative regulation of cell growth 3. In hematologic malignancies, SIPA1 mutations cause juvenile myelomonocytic leukemia, and Sipa1 deficiency in mice leads to age-dependent myeloproliferative neoplasm 4. Mechanistically, loss of Sipa1 in the bone marrow microenvironment alters mesenchymal stem cells and impairs niche homeostasis, enabling clonal hematopoietic evolution 4. In solid tumors, elevated SIPA1 promotes metastatic progression: in oral squamous cell carcinoma, SIPA1 overexpression drives invasion and migration through upregulation of integrin β1 and matrix metalloproteinase 7 5. Conversely, reduced SIPA1 expression in gastric and colorectal cancers correlates with tumor progression and poor prognosis 6 7. In colorectal cancer, UCHL3-mediated stabilization of SIPA1 promotes proliferation and metastasis, suggesting a therapeutic axis targeting post-translational SIPA1 regulation 7. SIPA1 genetic variants, particularly rs746429 and rs3741378, associate with breast cancer susceptibility 8 9.