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Dysregulated fatty acid metabolism interacts with oncogenic signals, thereby worsening tumor aggressiveness. The stearoyl-CoA desaturating enzymes, SCD1 and SCD5, convert of saturated fatty acids to monounsaturated fatty acids. While SCD1 is frequently overexpressed in tumor cells and has been widely studied, SCD5 has both limited expression and poor characterization. Here we evaluated, in vitro and in vivo, the effects of SCD5 overexpression in a metastatic clone of 4T1. The results showed SCD5-driven reprogramming of fatty acid metabolism, involving desaturation of stearic acid to oleic acid, which eventually blocked SPARC secretion. The latter event reduced the aggressiveness of the 4T1 subclone by decreasing the ECM deposition and reverting the Epithelial to Mesenchymal Transition (EMT) status. Variation of the fatty acid profile by SCD5-gene transduction or the direct administration oleic acid reduces the immune suppressive activity of myeloid cells and promoting granulocytic myeloid-derived suppressor cell maturation, eventually favoring T-cell activation. The less immunosuppressive microenvironment generated by SCD5 overexpression was enhanced in Sparc-KO mice, indicating that both extracellular and endogenous SPARC additively regulate myeloid cell-suppressive activities. Overall, our data sheds light on exploring the oleic acid-dependent inhibition of SPARC secretion as a possible mechanism to reduce breast cancer malignancy.

Supplementary Figure 4 from The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms

Supplementary Methods, Figure Legends 1-3, Table 1 from The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms

Supplementary Figure 2 from The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms

Supplementary Figure 1 from The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms

The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense “antagomir” oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma. [Cancer Res 2008;68(8):2745–10]

Supplementary Figure 3 from The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms