PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR

• Published in: Breast cancer research : BCR Vol. 26; no. 1; p. 34
• Main Authors: Edwards, Courtney M, Kane, Jeremy F, Smith, Jailyn A, Grant, Déja M, Johnson, Jasmine A, Diaz, Maria A Hernandez, Vecchi, 3rd, Lawrence A, Bracey, Kai M, Omokehinde, Tolu N, Fontana, Joseph R, Karno, Breelyn A, Scott, Halee T, Vogel, Carolina J, Lowery, Jonathan W, Martin, T John, Johnson, Rachelle W
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26-02-2024; BioMed Central; BMC
• Subjects: Amino acids; Apoptosis; Breast cancer; Breast Neoplasms - pathology; C-Terminus; Cancer; Care and treatment; Cell growth; Cell Proliferation - genetics; Clinical outcomes; Development and progression; Female; Genes; Growth; Humans; Hypercalcemia; International economic relations; Leukemia; Leukemia inhibitory factor; Leukemia Inhibitory Factor Receptor alpha Subunit; Localization; Metastases; Metastasis; Nuclear Localization Signals; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - metabolism; Patients; Peptides; Plasmids; Proteins; Receptors, OSM-LIF; Scientific equipment and supplies industry; Smooth muscle; Tumor suppressor genes; Tumorigenesis; Tumors; United States
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-024-01791-z

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.