Progesterone impairs Herceptin effect on breast cancer cells

Kamila Kitowska-Marszałkowska , Agnieszka Kowalska , Magdalena Mieszkowska , Dominika Piasecka , Andrzej Składanowski , Hanna M. Romańska , Rafał Sądej

Abstract

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 G1 phase towards S and G2 phases with concomitant upregulation of cyclin‑dependent kinase 2 (CDK2) and downregulation of CDK inhibitor p27Kip1. These results demonstrate for the first time PG involvement in the failure of Herceptin treatment in vitro. 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.
Author Kamila Kitowska-Marszałkowska KBM
Kamila Kitowska-Marszałkowska,,
- Department of Medical Biotechnology
, Agnieszka Kowalska MWB UG i GUMed
Agnieszka Kowalska,,
- Intercollegiate Faculty of Biotechnology UG
, Magdalena Mieszkowska MWB UG i GUMed
Magdalena Mieszkowska,,
- Intercollegiate Faculty of Biotechnology UG
, Dominika Piasecka
Dominika Piasecka,,
-
, Andrzej Składanowski KBM
Andrzej Składanowski,,
- Department of Medical Biotechnology
, Hanna M. Romańska
Hanna M. Romańska,,
-
, Rafał Sądej KBM
Rafał Sądej,,
- Department of Medical Biotechnology
Journal seriesOncology Letters, ISSN 1792-1074
Issue year2018
Vol15
No2
Pages1817-1822
Publication size in sheets0.5
Keywords in Englishprogesterone, human epidermal growth factor receptor 2, breast cancer, Herceptin resistance
DOIDOI:10.3892/ol.2017.7493
URL https://www.spandidos-publications.com/10.3892/ol.2017.7493/download
Languageen angielski
Score (nominal)15
ScoreMinisterial score = 15.0, 09-02-2018, ArticleFromJournal
Ministerial score (2013-2016) = 15.0, 09-02-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 1.39 (2) - 2016=1.495 (5)
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