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Research Paper|Volume 12, Issue 24|pp 24671—24692

Progesterone receptor isoform-dependent cross-talk between prolactin and fatty acid synthase in breast cancer

Javier A. Menendez1,2, Susan K. Peirce3, Adriana Papadimitropoulou4, Elisabet Cuyàs1,2, Travis Vander Steen5, Sara Verdura1,2, Luciano Vellon6, Wen Y. Chen7, Ruth Lupu5,8,9
  • 1Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
  • 2Girona Biomedical Research Institute (IDIBGI), Girona, Spain
  • 3Peirce Medical Communications, Clemson, SC 29634, USA
  • 4Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
  • 5Mayo Clinic, Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USA
  • 6Stem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires, Argentina
  • 7Department of Biological Sciences, Clemson University, Greenville, SC 29634, USA
  • 8Mayo Clinic Minnesota, Department of Biochemistry and Molecular Biology Laboratory, Rochester, MN 55905, USA
  • 9Mayo Clinic Cancer Center, Rochester, MN 55905, USA
* Equal contribution
Received: September 23, 2020Accepted: October 27, 2020Published: December 10, 2020
https://doi.org/10.18632/aging.202289

Copyright: © 2020 Menendez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.