E2 + norethisterone promotes the PI3K-AKT pathway via PGRMC1 to induce breast cancer cell proliferation.

Abstract

OBJECTIVE:

This study aimed to find evidence that progesterone receptor membrane component 1 (PGRMC1) promotes estradiol (E2) + norethisterone (NET)-induced breast cancer proliferation through activation of the phosphatidylinositol-3-kinase (PI3K)-AKT pathway.

METHODS:

PGRMC1-mediated breast cancer cellular proliferation and phosphorylation of PGRMC1 were studied using wild-type (hemagglutinin [HA]-tagged) MCF-7 cells, which were stably transfected with expression vector containing HA (MCF-7-HA cells), PGRMC1 (MCF-7-PGRMC1 cells) and Ser181 point mutated PGRMC1 (MCF-7-PGRMC1-S181A cells). Bioinformatics, cell proliferation, western blot, isobaric tags for relative and absolute quantitation (iTRAQ)-based RNA sequencing, real-time quantitative polymerase chain reaction (RT-qPCR) and cell cycle in vitro assays were performed to indicate the function of PGRMC1 and its possible mechanisms in breast cancer.

RESULTS:

NET + E2 elicited a significant proliferation in MCF-7-Vec at 10-6 M and 10-10 M, respectively. MCF-7-PGRMC1 did increase the phosphorylation of AKT or ERK, which can be blocked by treatment with casein kinase 2 (CK2) inhibitor quinalizarin or in MCF-7-PGRMC1-S181A cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the PI3K-AKT pathway is upregulated in MCF-7-PGRMC1 cells. Importantly, upregulation of the PI3K-AKT pathway mainly through promotion of cell cycle regulation strongly promoted cell proliferation in MCF-7-PGRMC1 cells.

CONCLUSIONS:

CK2 is involved in phosphorylation of PGRMC1 at S181. The mechanism for the action of PGRMC1 for mediating proliferative progestogen effects obviously starts with promotion cell cycle regulation, and then activation of the PI3K-AKT pathway.

• Authors: L Zhang, X Ruan, M Gu, A O Mueck
• Journal: Climacteric : the journal of the International Menopause Society (Climacteric) Vol. 25 Issue 5 Pg. 467-475 (10 2022) ISSN: 1473-0804 [Electronic] England
• PMID: 35137666 (Publication Type: Journal Article)

Chemical References

• Membrane Proteins
• PGRMC1 protein, human
• Receptors, Progesterone
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Norethindrone

Topics

• Breast Neoplasms (metabolism)
• Cell Proliferation
• Female
• Humans
• MCF-7 Cells
• Membrane Proteins
• Norethindrone
• Phosphatidylinositol 3-Kinase (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism, pharmacology)
• Proto-Oncogene Proteins c-akt (pharmacology)
• Receptors, Progesterone