The study aimed to identify genes that mediate lung metastasis in breast cancer cells and correlate with the propensity of primary human breast cancers to relapse in the lungs. The MDA-MB-231 cell line, derived from a breast cancer patient with widespread metastasis, was used to select cells with distinct metastatic abilities and tissue tropisms. Through a series of in vivo and in vitro experiments, a gene expression signature associated with lung metastasis was identified. This signature included 95 unique genes, 48 of which were overexpressed and 47 underexpressed in highly metastatic populations. Functional validation of a subset of these genes, including epiregulin (EREG), GRO1/CXCL1, MMP1, SPARC, IL13Ra2, and VCAM1, showed that they mediate lung metastasis. The study also found that a clinically relevant subgroup of primary breast tumors expressed this lung metastasis signature, and those tumors had poorer lung-metastasis-free survival. Additionally, the authors observed that some genes in the signature might facilitate both breast tumorigenicity and lung metastasis, while others confer growth advantages specifically in the lung microenvironment. These findings provide insights into the biology of breast cancer metastasis and potential targets for treatment.The study aimed to identify genes that mediate lung metastasis in breast cancer cells and correlate with the propensity of primary human breast cancers to relapse in the lungs. The MDA-MB-231 cell line, derived from a breast cancer patient with widespread metastasis, was used to select cells with distinct metastatic abilities and tissue tropisms. Through a series of in vivo and in vitro experiments, a gene expression signature associated with lung metastasis was identified. This signature included 95 unique genes, 48 of which were overexpressed and 47 underexpressed in highly metastatic populations. Functional validation of a subset of these genes, including epiregulin (EREG), GRO1/CXCL1, MMP1, SPARC, IL13Ra2, and VCAM1, showed that they mediate lung metastasis. The study also found that a clinically relevant subgroup of primary breast tumors expressed this lung metastasis signature, and those tumors had poorer lung-metastasis-free survival. Additionally, the authors observed that some genes in the signature might facilitate both breast tumorigenicity and lung metastasis, while others confer growth advantages specifically in the lung microenvironment. These findings provide insights into the biology of breast cancer metastasis and potential targets for treatment.