Abstract P6-14-03: Oestrogen represses Noggin expression by interfering BMP/Smad signalling in ER positive breast cancer cells

Abstract

Abstract Background Bone morphogenetic proteins (BMPs) are members of Transforming Growth Factor β (TGF-β) superfamily. BMPs are actively involved in the disease progression and bone metastasis of breast cancer. As a natural antagonist of BMP, Noggin plays important roles in the regulation of BMP signalling. It can facilitate spread of breast cancer cells to bone and subsequent colonisation and formation of osteolytic bone lesions. The present study aimed to investigate the regulatory mechanism for Noggin expression in oestrogen receptor (ER) positive breast cancer cells. Method Noggin expression was analysed in The Cancer Genome Atlas (TCGA ER (+) n=763, ER (-) n=216) and E-MTAB-6703 (ER (+) n=733, ER (-) n=421) cohorts. Correlation between Noggin and ER was evaluated using Spearman test. The expression of Noggin in an ER positive breast cancer cell line MCF-7 was determined by depriving the cells from oestrogen using phenol red-free DMEM supplemented with 10% charcoal stripped foetal calf serum or adding 10-10M 17-β-oestradiol. Activation of Smad-1/5/8 and involvement of BMP receptors in the oestrogen repressed Noggin expression were further examined using recombinant human BMP7 and a BMP receptor inhibitor (LDN-193189). Influence of Noggin on cellular functions was evaluated in MCF-7 cells with Noggin overexpression using a lentiviral Noggin expression vector. Results Noggin expression was negatively correlated with ERα in both TCGA BRCA (r=-0.162, p<0.01, n=1093) and E-MTAB-6703 (r=-0.078, p<0.01, n=2302) cohorts. The expression of Noggin was increased in the MCF-7 cells upon a deprivation from oestrogen which was further validated by adding 17-β-oestradiol. This is in line with the increased expression of Noggin observed in the MCF-7 cells with ER silencing (GSE27473). Furthermore, an increased level of phosphorylated Smad1/5/8 was seen in the MCF-7 being hungered from oestrogen which was prevented by adding 17-β-oestradiol and LDN-193189, respectively. As a result, the oestrogen hunger induced Noggin expression was also decreased by adding with 17-β-oestradiol and LDN-193189. To further investigate the influence of oestrogen on BMP-Smad signalling regulated Noggin expression, Noggin expression and phosphorylation of Smad1/5/8 and Smad3 were determined in MCF-7 cells which were treated with rhBMP7 and in combination with 17-β-oestradiol and LDN-193189, respectively. BMP7 induced Noggin expression and activation of Smad1/5/8 can be diminished by 17-β-oestradiol and LDN-193189. Noggin overexpression in MCF-7 cells resulted in an increase of proliferation. Conclusion Noggin expression can be repressed by oestrogen through an inference of the BMP- Smad signalling. Overexpression of Noggin promoted proliferation of MCF-7 cells. Further investigation is required to clarify the exact role of Noggin in ER positive breast cancer and its implication in the disease progression and current therapies. Citation Format: Ming Liu, Lin Ye, Wen G. Jiang. Oestrogen represses Noggin expression by interfering BMP/Smad signalling in ER positive breast cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-03.