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

• Published in: Aging (Albany, NY.) NY.), 2020-12, Vol.12 (24), p.24671-24692
• Main Authors: Menendez, Javier A, Peirce, Susan K, Papadimitropoulou, Adriana, Cuyàs, Elisabet, Steen, Travis Vander, Verdura, Sara, Vellon, Luciano, Chen, Wen Y, Lupu, Ruth
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.202289

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 T47D 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 T47D 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 T47D 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.