Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant synthesis, processing and signaling of hyaluronan (HA). Hyaluronan Mediated Motility Receptor (RHAMM, HMMR) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression to breast tumor progression, however cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirms increased RHAMM expression correlates with aggressive clinicopathological features. To probe mechanisms, we develop a novel 27-gene RHAMM-related signature (RRS) by intersecting differentially expressed genes in lymph node (LN) positive patient cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validate in an independent cohort. We demonstrate RRS predicts for poor survival and is enriched for cell cycle and TME-interaction pathways. Further analyses using CRISPR/Cas9 generated RHAMM−/− breast cancer cells provide direct evidence that RHAMM promotes invasion in vitro and in vivo. Immunohistochemistry studies highlight heterogeneous RHAMM protein expression, and spatial transcriptomics associates the RRS with RHAMM-high microanatomic foci. We conclude RHAMM upregulation leads to the formation of ‘invasive niches’, which are enriched in RRS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes.