Levonorgestrel-induced modulation of triple negative breast cancer proliferation via glucocorticoid receptor.

Indiscriminate use of levonorgestrel, a progestin-only contraceptive, can affect breast cancer subtypes, as it can plausibly bind to steroid receptors other than Estrogen Receptor (ER) and Progesterone Receptor (PR). The ER, PR negative status of TNBC makes it important to explore other receptors of levonorgestrel. In this study glucocorticoid receptor (GR) was observed to show - 83.519 kcal/mol free energy of binding with levonorgestrel. To understand the effect of levonorgestrel on breast cancer cells, cellular assays were performed. In the cell proliferation assays, it was found that ER + PR + Her2- cell line, MCF-7, showed reduced proliferation upon treatment with levonorgestrel for 24 h. Whereas TNBC cell lines (MDA-MB-231 and MDA-MB-468) showed statistically significantly higher proliferation rate. Cellular adhesion assays displayed more adhesion in levonorgestrel-treated MCF-7 cells than in levonorgestrel-treated MDA-MB-231 and MDA-MB-468, as compared to the control. Ki67 (proliferation marker) showed upregulation in MCF-7 control. Levonorgestrel-treated MCF-7 cells demonstrated Ki67 downregulation. In contrast, the treatment triggered upregulation of Ki67 in TNBC cell lines on levonorgestrel treatment. Therefore, the study suggests that in the absence of ER and PR in TNBC, levonorgestrel may potentially show its effect through GR. The study emphasizes the need for further research, as there exist several factors, such as the consumption of oral contraceptive pills like levonorgestrel, which might worsen the status of breast cancer in women. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04447-7.