Research Paper Volume 12, Issue 24 pp 24671—24692
Progesterone receptor isoform-dependent cross-talk between prolactin and fatty acid synthase in breast cancer
- 1 Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
- 2 Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- 3 Peirce Medical Communications, Clemson, SC 29634, USA
- 4 Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- 5 Mayo Clinic, Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USA
- 6 Stem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires, Argentina
- 7 Department of Biological Sciences, Clemson University, Greenville, SC 29634, USA
- 8 Mayo Clinic Minnesota, Department of Biochemistry and Molecular Biology Laboratory, Rochester, MN 55905, USA
- 9 Mayo Clinic Cancer Center, Rochester, MN 55905, USA
Received: September 23, 2020 Accepted: October 27, 2020 Published: December 10, 2020
https://doi.org/10.18632/aging.202289How to Cite
Abstract
Progesterone receptor (PR) isoforms can drive unique phenotypes in luminal breast cancer (BC). Here, we hypothesized that PR-B and PR-A isoforms differentially modify the cross-talk between prolactin and fatty acid synthase (FASN) in BC. We profiled the responsiveness of the FASN gene promoter to prolactin in T47Dco BC cells constitutively expressing PR-A and PR-B, in the PR-null variant T47D-Y cell line, and in PR-null T47D-Y cells engineered to stably re-express PR-A (T47D-YA) or PR-B (T47D-YB). The capacity of prolactin to up-regulate FASN gene promoter activity in T47Dco cells was lost in T47D-Y and TD47-YA cells. Constitutively up-regulated FASN gene expression in T47-YB cells and its further stimulation by prolactin were both suppressed by the prolactin receptor antagonist hPRL-G129R. The ability of the FASN inhibitor C75 to decrease prolactin secretion was more conspicuous in T47-YB cells. In T47D-Y cells, which secreted notably less prolactin and downregulated prolactin receptor expression relative to T47Dco cells, FASN blockade resulted in an augmented secretion of prolactin and up-regulation of prolactin receptor expression. Our data reveal unforeseen PR-B isoform-specific regulatory actions in the cross-talk between prolactin and FASN signaling in BC. These findings might provide new PR-B/FASN-centered predictive and therapeutic modalities in luminal intrinsic BC subtypes.