THE LINK OF FATTY ACID AND IRON METABOLISM IN THE CONTEXT OF TAMOXIFEN RESISTANCE

Tamoxifen resistance represents a major clinical problem during hormone therapy treatment. We have developed an in vitro model of tamoxifen-resistance in estrogen positive breast cancer cell lines MCF7 and T47D resistant to 5 µM tamoxifen (Tam5R cells). We have found that Tam5R cells show altered fatty acid metabolism, in particular in metabolism of glycerol phospholipids. Furthermore, we have identified that these cells have altered iron metabolism and asked whether there is an interplay between these phenomena. Our data showed a consistent up-regulation of enzymes involved in fatty acid synthesis such as ACSL1 and ACSS1 in Tam5R cells. At the same time, we have documented higher mitochondrial iron stores but lower iron utilization in these cells. Therefore, we have analyzed the response of ACSS1 and ACSL1 to iron deprivation and iron overload in wild-type and Tam5R cells. Interestingly, our data show that both ACSL1 and ACSS1 respond to iron deprivation and iron excess. ACSS1 seems to follow similar pattern as ACO2, a well-known iron-regulated mitochondrial enzyme, with IRE located at  5´ UTR. On the other hand, ACSL1 seems to show a pattern similar to TFR1, an iron-regulated transferrin receptor, whose mRNA stability is regulated by IRE present at 3´ UTR. Therefore, we propose that there is an interplay between fatty acid synthesis and iron metabolism which is disrupted in the context of tamoxifen resistance and may be regulated by the IRE/IRP system.

Funding:  Funded by Czech Science Foundation project no. 23-06208S and MEYS Program EXCELES LX22NPO5102.