Background Cancer-associated Þbroblasts (CAFs) are known to impact on tumour behaviour but mechanisms controlling this are poorly understood. Methods Breast normal fibroblasts (NFs) or CAFs were isolated from cancers by laser-microdissection or were cultured. Fibroblasts were transfected to manipulate miR-222 or Lamin B Receptor (LBR). Fibroblast conditioned medium was collected and used to treat epithelial BC lines MDA-MB-231 and MDA-MB-157. Migration, invasion, proliferation, or senescence was assessed using transwell, MTT or X-gal assays respectively. Results MiR-222 was up-regulated in CAFs as compared to NFs. Ectopic miR-222 expression in NFs induced CAF-like expression profiles, while miR-222 knock-down in CAFs inhibited CAF phenotypes. LBR was identified as a direct miR-222 target and was functionally relevant since LBR knock-down phenocopied miR-222 over-expression and LBR over-expression phenocopied miR-222 knock-down. MiR-222 over-expression, or LBR knock-down, was sufficient to induce NFs to show CAF characteristics of enhanced migration, invasion and senescence, and furthermore conditioned medium from these fibroblasts induced increased BC cell migration and invasion. The reverse manipulations in CAFs inhibited these behaviours in fibroblasts and inhibited paracrine influences on BC cells. Conclusion MiR-222/LBR have key roles in controlling pro-progression influences of CAFs in BC. This pathway may present therapeutic opportunities to inhibit CAF-induced cancer progression. 3 BACKGROUND Breast cancer (BC) is the leading cause of cancer death worldwide among women 1 , and nearly 2.3 million females are newly diagnosed annually. Although there are initial responses to treatment, many cancers relapse and distant metastases occur in nearly one third of woman; these are typically fatal. The biology behind BC metastases still remains undetermined. Therefore, understanding molecular determinants of metastasis is crucial for finding new therapeutic strategies. The tumour microenvironment consists of immune cells, blood vessels, endothelial cells, fibroblasts and extracellular matrix 4. This microenvironment plays key roles in disease outcome by inducing tumour cell proliferation and aggressiveness 5,6. Cancer-associated Þbroblasts (CAFs), an activated form of tissue-resident fibroblasts present within breast cancers, comprise a major component of the tumour microenvironment 7 , characterised most commonly by expression of-smooth muscle actin 8. CAFs can induce cancer progression 9 and metastasis 10 by secreting various cytokines, chemokines and growth factors (e.g. VEGF, FGF2, TGF , CXCL12, IL6 and IL8) 11,12 and by modulating the extracellular matrix (ECM) that facilitates tumour cell migration and invasion 13,14. CAFs also modulate immune cell function to create an immune suppressive environment during cancer progression 15. The process of transformation of CAFs from resident normal Þbroblasts is achieved by several growth factors 16,17,18 , however mechanisms of transformation have not yet been fully expl...

This is a repository copy of Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy.

This is a repository copy of MiR-19b non-canonical binding is directed by HuR and confers chemosensitivity through regulation of P-glycoprotein in breast cancer.

Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.