Simple SummaryBreast cancer is one of the most common malignant tumors in women, and metastatic breast cancer usually has a poor prognosis. Hence, it is urgent to identify new biomarkers to promote precise medication in breast cancer. LHX2 has been reported to promote the proliferation of numerous solid tumors, but its role in breast cancer has not been elucidated. Our study explored the prognostic value and the immune cell infiltration of breast cancer related to LHX2. We found that LHX2 can serve as an independent prognostic factor in breast cancer. In vitro and in vivo experiments confirmed that LHX2 promoted cell proliferation, migration ability, and invasive ability but inhibited apoptosis in breast cancer. Immunohistochemistry and immunofluorescence experiments were conducted to investigate LHX2-related immune infiltration in breast cancer tissues. A Western blot assay proved that LHX2 activated the PI3K/AKT/mTOR pathway and the apoptosis pathway.AbstractWorldwide, breast cancer is the most common malignancy. LHX2, a member of the LIM homeobox gene family and a transcription factor, plays a crucial role in numerous tumors, but the function of LHX2 in breast cancer progression remains unknown. In this study, we show that LHX2 is upregulated in breast cancer tissues and positively correlated with breast cancer progression. Meanwhile, the clinical characteristics of breast cancer and LHX2 expression showed a strong correlation. GSEA showed that a high LHX2 expression may activate the T-cell activation pathway, PI3K/AKT/mTOR signaling pathway, and apoptosis pathway. Moreover, ssGSEA showed that Th1 cells and Th2 cells had a positive correlation with LHX2 expression in breast cancer. Experiments showed that LHX2 promotes the proliferation, colony formation, migration, and invasion of breast cancer cells. Immunohistochemistry and immunofluorescence assays helped to analyze LHX2-associated immune infiltration in breast cancer. A Western blot assay proved that LHX2 activated the PI3K/AKT/mTOR pathway and the apoptosis pathway. A TUNEL assay confirmed that LHX2 inhibited apoptosis. Taken together, LHX2 plays a vital role in breast cancer’s progression and prognosis and could be an immune infiltration biomarker for breast cancer, and LHX2 activates the PI3K/AKT/mTOR pathway and apoptosis pathway in breast cancer.