Exposure　to　bisphenol　A　(BPA)　is　considered　to　be　associated　with　the　increased　incidence　of　breast　cancer.　As　a　widespread　replacement　of　BPA,　the　effect　of　bisphenol　S　(BPS)　on　breast　tumor　programming　has　not　been　studied.　We　reported　that　BPS　exposure　significantly　promoted　proliferation　and　deterioration　of　breast　tumor　by　nonmonotonic　dose　response.　The　mechanisms　were　investigated　by　molecular　biology　and　mass　spectrometry-based　lipidomics,　proteomics　and　imaging.　BPS　exposure　induced　the　spatially　intratumor　heterogeneity　of　morphology-driven　lipids　and　proteins.　The　more　significant　proliferation　resulted　from　BPS-10　(10　μg/kg　body　weight　/day)　exposure　was　evidenced　by　the　variations　of　spatial　distribution　of　lipids　related　to　ceramide-sphingomyelin　signaling　pathway,　proteins　related　to　chromosomal　stability　and　cell　proliferation　in　central　necrotic　regions　of　breast　tumor.　In　contrast,　the　BPS-100　exposure　obviously　accelerated　deterioration　of　breast　tumor　by　the　variations　of　spatial　distribution　of　proteins　that　were　associated　with　the　stability　of　nucleic　acid　structure　in　peripheral　neoplastic　regions.　Accordingly,　dysregulation　of　metabolism　and　protein　function　as　well　as　DNA　methylation　and　hypoxic　tumor　microenvironment　could　be　applied　to　predict　the　possibility　of　tumorigenesis,　proliferation　and　metastasis　that　might　be　caused　by　other　bisphenol　analogs.　©　2021　Elsevier　B.V.