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Late recurring ER+ breast cancer emerges in post-menopausal women despite low/no hormone conditions. Cancer associated fibroblasts (CAFs) represent a major player in the promotion of metastasis, stemness and chemotherapy resistance in breast cancer. Progesterone receptors (PR) are emerging as drivers of stemness and metastasis in ER+ breast cancers. We propose that CAFs provide a mechanism to turn on ligand-independent PR signaling pathways through the secretion of paracrine factors.

Methods: Tumorsphere assays were used to measure stem cell expansion. Cell clustering assays were used to measure CAF/tumor cell interactions. ChIP assays were used to measure PR direct binding to stemness gene regulatory elements.

Results: Using the ER(+) T47D cell series (i.e., PR-null variants or cells expressing either endogenous PR (T47DCO) or PR-A or PR-B isoforms), we observed that CAF …