Progesterone Receptor Membrane Component 1 Promotes Cell Proliferation and Tamoxifen Resistance through Alteration of Sexual Receptors in Breast Cancer

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URI: http://hdl.handle.net/10900/136669
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1366694
http://dx.doi.org/10.15496/publikation-78020
Dokumentart: PhDThesis
Date: 2023-02-20
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Seeger, Harald (Prof. Dr.)
Day of Oral Examination: 2022-11-10
DDC Classifikation: 610 - Medicine and health
Keywords: Brustkrebs , Proliferation , Hormontherapie , Tamoxifen , Résistance , Estradiol , Progesteron , Medroxyprogesteron
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Abstract:

Breast cancer remains the leading malignancy in women around the world. Since over two thirds of breast cancers are estrogen receptor-α (ER-α) positive and higher incidence is found in postmenopausal women, endocrine therapy is the mainstay of adjunctive therapy for this population. However, resistance with longer treatment has aroused wide concern and is not yet fully understood. Progesterone receptor membrane component 1 (PGRMC1) as an upregulated membrane bound protein in tumorigenesis and progression has been reported to correlate with higher incidence of endocrine resistance. Thus, a better understanding of how PGRMC1 is involved in this process could help to stratify patients and guide decision making. The present study was undertaken to evaluate the impact of PGRMC1 overexpression (1) on the regulation of cell proliferation by 17-β estradiol (E2) and progestogens; (2) on the response to tamoxifen (TAM) treatment; (3) on the regulation of ER-α, progesterone receptor (PR) and intrinsic PGRMC1 expression by E2 and progestogens so as to discover the possible correlation between PGRMC1 and sexual hormone signaling pathways in breast cancer, as well as to investigate a tentative role of PGRMC1 in endocrine resistance. The present study was undertaken in empty vector or PGRMC1 transfected estrogen receptor (ER) positive breast cancer cells, ie. MCF-7ECV, T47DEVC, MCF-7WT12, and T47DWT3 cells. Cells were incubated with single E2 or progestogens, and with TAM plus E2 for 5 days. Progestogens used in the present study included progesterone (P4), medroxyprogesterone acetate (MPA) and norethisterone (NET). E2 was used at 10-9 M, and other agents were used at 10-7 M and 10-6 M. Cell proliferation was measured by Methyl thiazoletetrazolium (MTT) test. Expressions of ER-α, PR and PGRMC1 were measured by western blot. SPSS statistical software 23.0 was used for quantitative analysis. Multi-group comparison was carried out using ANVOA followed by Bonferroni test. P<0.05 was considered statistically significant. Results showed that 1) E2 as well as MPA and NET significantly promoted proliferation in all cells, whereas P4 demonstrated promoting effect only in MCF-7WT12 and T47DWT3 cells. When treated with TAM plus E2, significant promoted cell proliferations were only observed in MCF-7WT12 and T47DWT3 cells. 2) In MCF-7WT12 and T47DWT3 cells, no significant signals were observed for progesterone receptor A (PRA) and progesterone receptor B (PRB) either before or after any treatment. 3) E2 significantly upregulated ER-α and intrinsic PGRMC1 expressions in all cells and upregulated PRA and PRB expressions in MCF-7EVC and T47DEVC cells. 4) All progestogens downregulated ER-α expression in all the cells. P4, NET and MPA significantly downregulated intrinsic PGRMC1 expression in MCF-7EVC and T47DEVC cells, whereas significantly upregulated intrinsic PGRMC1 expression in MCF-7WT12 and T47DWT3 cells. P4 significantly downregulated, whereas NET and MPA significantly upregulated PRA and PRB expressions in MCF-7EVC and T47DEVC cells. 5) E2 plus TAM significantly upregulated ER-α and downregulated PGRMC1 expressions in MCF-7EVC and T47DEVC cells, whereas no significant changes were observed in MCF-7WT12 and T47DWT3 cells; PRA and PRB expressions were significantly downregulated in MCF-7EVC and T47DEVC cells. In conclusion, PGRMC1 overexpression adds to the promoting effects of cell proliferation by E2 and synthetic progestins in breast cancer. TAM and P4 lose antiproliferative effect in the status of PGRMC1 overexpression. E2 and progestogens have diverse regulatory actions on PGRMC1 expression, whereas in PGRMC1 overexpression status progestogens lose suppressing action of PGRMC1 expresson. In addition, PGRMC1 overexpression seems to impel loss of ER-α and PR, which indicates the potential inactivation of ER-α signaling pathway and might be one of the main mechanisms of TAM resistance. Thus, in the clinical aspect, determination of PGRMC1 overexpression so as to identify the breast cancer population at higher risk of disease progression and TAM resistance is of great value. P4 might be a safer option than synthetic progestins, however in the condition of PGRMC1 overexpression, cautions should be taken when prescribing sexual hormones.

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