Abstract P1-06-06: Meta-analysis reveal novel mechanism of bisphenol A effect on mammary gland

Abstract

Abstract Pubertal exposure to bisphenol A (BPA) has been shown to cause abnormal mammary gland development and neoplastic transformation in adults. However, the mechanism of this BPA effect still remains largely unknown. We exposed 21-day-old Balb/c mice to BPA by gavage (25 µg/kg/day) during puberty for 3 weeks. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age and subsequently sorted into Lin-CD49f-CD24-stromal cells, Lin-CD49fhighCD24med MaSCs-enriched basal cells and Lin-CD49flowCD24high luminal progenitor-enriched cells with FACS for gene expression analysis. The Gene Ontology (GO) Enrichment Analysis shows that upon BPA treatment, the biological processes (BPs) significantly enriched in luminal compartment were related to response to organic substance and hormone stimuli at early stage (2 month old) whereas to cell cycle regulation at late stage (4 month old), consistent with published study in mammary gland morphology where BPA promoted the expansion of luminal population. However, the BPs enriched in spheres derived from basal cells (highly enriched with MaSCs) collected at late stage (4 month old) were mainly related to cell adhesion, epithelial differentiation and in stromal cells were related with vascular development for tissues collected either immediately after BPA treatment or 6 weeks later at 4-month of age. More interestingly, the Downstream Function Effects Analysis performed by Ingenuity Pathway Analysis reveal the changes in any compartments will all lead to significant activation of cancer-related downstream effects including hyperplasia, neoplasm of mammary tumor, proliferation of tumor cells and invasion of breast cancer, although there are few overlapping common genes in these compartments and conditions upon BPA treatment, indicating the different mechanism in response to BPA treatment and tumorigenesis. Network analysis revealed that the potential upstream regulators for these enriched BPs are TGFβ1, VEGF, PPARG, Estrogen/ Estrogen Receptor, glucocorticoid, ERK and NOTCH signaling. Together with our recently published data, this study reveals the difference in immediate and delayed response to pubertal BPA treatment and indicates that cross-talk between several growth factor and hormonal receptor signaling pathways may contribute to the altered cellular processes by BPA, consistent with the role of BPA as an endocrine disruptor. Citation Format: Xiang Gu, Hui Gao, Danhan Wang, Abhik Bandyopadhyay, Qiaoxiang Dong, LuZhe Sun. Meta-analysis reveal novel mechanism of bisphenol A effect on mammary gland [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-06-06.