Obese women diagnosed with breast cancer have an increased risk for metastasis, and the underlying mechanisms are not well established. Within the mammary gland, adipose-derived stromal cells (ASCs) are heterogeneous cells with the capacity to differentiate into multiple mesenchymal lineages. To study the effects of obesity on ASCs, mice were fed a control diet (CD) or high-fat diet (HFD) to induce obesity, and ASCs were isolated from the mammary glands of lean and obese mice. We observed that obesity increased ASCs proliferation, decreased differentiation potential, and upregulated expression of α-smooth muscle actin, a marker of activated fibroblasts, compared to ASCs from lean mice. To determine how ASCs from obese mice impacted tumor growth, we mixed ASCs isolated from CD- or HFD-fed mice with mammary tumor cells and injected them into the mammary glands of lean mice. Tumor cells mixed with ASCs from obese mice grew significantly larger tumors and had increased invasion into surrounding adipose tissue than tumor cells mixed with control ASCs. ASCs from obese mice demonstrated enhanced tumor cell invasion in culture, a phenotype associated with increased expression of insulin-like growth factor-1 (IGF-1) and abrogated by IGF-1 neutralizing antibodies. Weight loss induced in obese mice significantly decreased expression of IGF-1 from ASCs and reduced the ability of the ASCs to induce an invasive phenotype. Together, these results suggest that obesity enhances local invasion of breast cancer cells through increased expression of IGF-1 by mammary ASCs, and weight loss may reverse this tumor-promoting phenotype.
The Hedgehog signaling pathway is part of the ancient developmental-evolutionary animal toolkit. Frequently co-opted to pattern new structures, the pathway is conserved among eumetazoans yet flexible and pleiotropic in its effects. The Hedgehog receptor, Patched, is transcriptionally activated by Hedgehog, providing essential negative feedback in all tissues. Our locus-wide dissections of the cis-regulatory landscapes of fly patched and mouse Ptch1 reveal abundant, diverse enhancers with stage- and tissue-specific expression patterns. The seemingly simple, constitutive Hedgehog response of patched/Ptch1 is driven by a complex regulatory architecture, with batteries of context-specific enhancers engaged in promoter-specific interactions to tune signaling individually in each tissue, without disturbing patterning elsewhere. This structure—one of the oldest cis-regulatory features discovered in animal genomes—explains how patched/Ptch1 can drive dramatic adaptations in animal morphology while maintaining its essential core function. It may also suggest a general model for the evolutionary flexibility of conserved regulators and pathways.DOI:
http://dx.doi.org/10.7554/eLife.13550.001
The OLE1 gene in Saccharomyces cerevisiae encodes the ∆9 desaturase, which inserts a double bond in saturated fatty acids to create unsaturated fatty acids (UFAs). OLE1 expression is controlled in part through the transcriptional regulators Mga2p and Spt23p in response to supply of UFAs. We investigated whether the regulation was uniform in response to different UFAs and at different concentrations. We found that in wild type cells, reporter gene assays show a stronger decrease in expression of OLE1 when fed 16:1∆9 or 18:2∆9, 12 as opposed to 18:1∆9 or 17:1∆10. Concentration of the fed fatty acid also impacted the regulation of OLE1 with higher levels of each UFA impacting expression to a greater degree. Fatty acid profiles of wild type cells show cells accumulate a higher concentration of 16:1∆9 and 18:2∆9, 12 than fed 18:1∆9 or 17:1∆10. This leads to the conclusion that the expression of OLE1 is dependent both on properties of fed fatty acids and the amount in the cell. While our initial hypothesis was that OLE1 is regulated in response to membrane fluidity, subsequent work does not support that idea. We have found that conditions that would affect membrane fluidity (besides UFA species and amount), such as growth temperature and saturated or trans fatty acid supplementation do not regulate OLE1 in the direction predicted by fluidity changes. Recently our lab has isolated a mutant that is deficient in regulation of OLE1, called nro1 (no regulation of OLE1). The signaling mechanism for the NRO1 protein’s action is unknown. Tests using the OLE1 promoter‐reporter gene constructs suggest that Nro1p responds more strongly to the fatty acids 16:1∆9 and 18:2∆9, 12, than 18:1∆9 and 17:1∆10. Characterization of NRO1 is discussed.
Grant Funding Source: Supported by NSF‐REU DBI‐0754293
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