Abstract
Short chain fatty acids (2 to 6 carbons in length) are ubiquitous lipids that are present in human plasma at micromolar concentrations. In addition to serving as metabolic precursors for lipid and carbohydrate synthesis, they also act as cognate ligands for two known G protein-coupled receptors (GPCRs), FFAR2 and FFAR3. While there is evidence that these receptors may inhibit the progression of colorectal cancer, their roles in breast cancer cells are largely unknown. We evaluated the effects of enforced overexpression of these receptors in two phenotypically distinct breast cancer cell lines: MCF7 and MDA-MD-231. Our results demonstrate that both receptors inhibit cell invasiveness, but through different signaling processes. In invasive, mesenchymal-like MDA-MB-231 cells, FFAR2 inhibits the Hippo-Yap pathway and increases expression of adhesion protein E-cadherin, while FFAR3 inhibits MAPK signaling. Both receptors have the net effect of reducing actin polymerization and invasion of cells through a Matrigel matrix. These effects were absent in the less invasive, epithelial-like MCF7 cells. Correspondingly, there is reduced expression of both receptors in invasive breast carcinoma and in aggressive triple-negative breast tumors, relative to normal breast tissue. Cumulatively, our data suggest that the activation of cognate receptors by short chain fatty acids drives breast cancer cells toward a non-invasive phenotype and therefore may inhibit metastasis.
Highlights
Metastasis is a multi-stage process involving genetically unstable tumor cells that undergo phenotypic changes that allow them to egress from the primary tumor and colonize a distant tissue site with a favorable microenvironment [1, 2]
To understand the functions of FFAR2 and FFAR3 in breast cancer metastasis, we evaluated two breast cancer cell lines that have contrasting epithelial-mesenchymal transition (EMT) phenotypes reflected by their EMT score: 1.0 = highly mesenchymal, -1.0 = highly epithelial [42]
As studies suggest that FFAR2 expression is reduced in certain cancers [30], and that proliferation may be inhibited by short chain fatty acids, butyrate and propionate [31, 43], we speculated that short chain fatty acid receptors might play a role in regulating breast cancer progression, and possibly metastasis
Summary
Metastasis is a multi-stage process involving genetically unstable tumor cells that undergo phenotypic changes that allow them to egress from the primary tumor and colonize a distant tissue site with a favorable microenvironment [1, 2]. Studies have implicated specific G protein-coupled receptors (GPCRs) as important mediators of EMT-related processes [12]. These include CXCR4, CCR7, PAR1 [13, 14], and receptors with bioactive lipid ligands, such as S1P1,3 [15,16,17], LPA1-6 [18, 19], and prostaglandin receptors (EP1 & EP4) [20, 21]. The short chain fatty acid butyrate is reported to inhibit growth and proliferation by inhibiting HDAC activity and inducing apoptosis [31, 34] Taken together these studies support a model by which reduced expression of FFAR2 and FFAR3 may contribute to cancer progression
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