An NCI-designated Comprehensive Cancer Center
By Jenny Wang | March 21, 2014

Jenny wangSuccessful breast cancer treatment is often hindered by chemoresistance, metastasis, and tumor recurrence.  The existence of a small population of cells, called cancer stem cells, is thought to contribute to these complications.  Cancer stems cells (CSCs), unlike the rest of the tumor bulk, have unlimited self-renewal capabilities and initiate tumors.  Many breast cancer therapies target the bulk of the tumor without killing the CSCs, allowing the tumor to eventually regenerate.

The transcription factor “signal transducer and activator of transcription 3” (STAT3) is known to be necessary for survival and proliferation of CSCs.  However, the mechanisms by which STAT3 can sustain cancer stem cells are not known.  After RNA-Seq was performed on STAT3 knockdown CSCs, I noticed that many lipid metabolic genes were affected, especially CPT1B (a transporter protein involved in the rate limiting step in fatty acid oxidation).  Fatty acid oxidation (FAO) is a metabolic process in which fats are broken down for energy.  By knocking down STAT3 in CSCs, I found that STAT3 can facilitate FAO by transcriptional activation of the enzyme CPT1B.  My research also indicates that breast cancer stem cells rely on STAT3-regulated FAO, while non-cancer stem cells do not.

While CSCs readily burn fat to sustain their metabolic demands, they do not actually have abundant fat stores.  Since breast cancer occurs in an adipose-rich environment, I hypothesized that breast adipocytes can promote CSC growth by providing substrates for FAO and other soluble factors.  My research shows that CSCs can directly uptake fatty acids from adipocytes.  In addition, coculturing CSCs with adipocytes induces rapid CSC proliferation and tropism to the adipocytes.  My research indicates that CSCs are metabolically distinct and can be targeted by metabolic manipulation, such as with the use of FAO inhibitors.  This opens new avenues of consideration for breast cancer therapy.