PPARγ maintains ERBB2-positive breast cancer stem cells

Abstract

Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor-γ (PPARγ)-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here, we report that inhibition of the PPARγ pathway reduces the aldehyde dehydrogenase (ALDH)-positive population in ERBB2-positive breast cancer cells. Results from in vitro tumorsphere formation assays demonstrate that the PPARγ antagonists GW9662 and T0070907 decrease tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells is partially due to ROS, as it can be rescued by treatment with N-acetyl-cysteine. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes, including ACLY, MIG12, FASN and NR1D1, and the stem-cell related genes KLF4 and ALDH in BT474 cells. Antagonist treatment also decreases the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2-positive breast cancer cells.

Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b

“…This suggests that TNBC cells have unique features that render them more sensitive to metformin action. Interestingly, CSCs have increased expression and reliance on lipogenic enzymes, including FASN [28, 29, 50, 51]. The ACACA/FASN-driven lipogenic switch couples the Warburg Effect to anabolic metabolism and enables conversion of somatic cells to stem cells [28].…”

Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists based on the helix12-folding inhibition hypothesis

“…Therefore, antagonists or inverse agonists targeting PPARg are considered to be candidates for treatment of osteoporosis and obesity [21,22]. Furthermore, PPARg antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment [23,24]. Therefore, the discovery of PPARg antagonists is of great interest in the search for candidate agents to treat PPARg-related diseases.…”

Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway

“…Many reports suggested PPARs modulation in cancer cells by either agonist or antagonist may be a potential treatment for metabolic diseases and cancer including BCa272829. Among those, the PPARγ pathway is particularly critical for the cancer stem cell properties of ErbB2-positive breast cancer cells3031, and has been reported to inhibit of ErbB activity in human breast cancer cells32.…”