Progesterone impairs Herceptin effect on breast cancer cells

• Published in: Oncology letters Vol. 15; no. 2; pp. 1817 - 1822
• Main Authors: Kitowska, Kamila, Kowalska, Agnieszka, Mieszkowska, Magdalena, Piasecka, Dominika, Skladanowski, Andrzej C, Romanska, Hanna M, Sadej, Rafal
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.02.2018; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Breast cancer; Care and treatment; Cell cycle; Cell growth; Development and progression; Gene expression; Genetic aspects; Health aspects; Hormones; Immunoglobulins; Kinases; Ligands; Medical prognosis; Monoclonal antibodies; Progesterone; Targeted cancer therapy; Tumors; United States > US; breast cancer; human epidermal growth factor receptor 2; Herceptin resistance; progesterone
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2017.7493

Breast cancer (BCa) is the most common cancer affecting women worldwide. Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in ~20-25% of invasive ductal breast carcinomas and is associated with the more aggressive phenotype. Herceptin, a humanized antibody against HER2, is a standard therapy in HER2-overexpressing cases. Approximately one-third of patients relapse despite treatment. Therefore numerous studies have investigated the molecular mechanisms associated with Herceptin resistance. An interaction between HER2 signalling and steroid hormone receptor signalling pathways has been previously investigated, but the effect of this relationship on Herceptin resistance has never been studied. The present study analysed an impact of the steroid hormone, progesterone (PG), on Herceptin-dependent cell growth inhibition. Results indicated that Herceptin-inhibited proliferation of breast cancer cell lines overexpressing HER2 (BT474 and MCF/HER2) in 3D culture is abolished by PG. Furthermore, results demonstrated that PG led to the activation of HER2/HER3-mediated signalling. Moreover, PG treatment induced a shift of Herceptin-dependent cell cycle arrest in G phase towards S and G phases with concomitant upregulation of cyclin-dependent kinase 2 (CDK2) and downregulation of CDK inhibitor p27 . These results demonstrate for the first time PG involvement in the failure of Herceptin treatment . The present observations suggest that cross-talk between PG- and HRG/HER2-initiated signalling pathways may lead to the acquisition of resistance to Herceptin in patients with BCa.