脂肪细胞通过携带miR-148a的外泌体降低乳腺癌细胞中ERα表达从而促进乳腺癌他莫昔芬耐药

As the main driving factor for the growth of ERα positive breast cancer cells, ERα is widely used as the drug target of endocrine therapy. Our previous study has demontrated that ERα is an important suppressor of breast cancer metastasis and loss of ERα in the invasive front of breast cancer promotes the amoeboid-like migration of cancer cells. However, the mechanism why ERα is lost is not clear. Our preliminary experiments suggest that adipocytes in the tumour microenvironment can secrete miR-148a containing exosomes and promote tamoxifen resistance in breast cancer by regulating the expression of ERα in breast cancer cells. Based on the previous study, we aim to systematically clarify that adipocyte-derived exosomal miR-148a promotes tamoxifen resistance in breast cancer by regulating the expression of ERα in breast cancer cells through the in vitro and in vivo assays. By studying the interaction between adipocytes and breast cancer cells in the microenvironment, our study might elucidate the mechanism of ERα loss, and might also extend the role of adipocytes in breast cancer tamoxifen resistance, which provides a new mechanism of tamoxifen resistance and a new idea to solve the problem.

ERα信号通路是ERα阳性乳腺癌细胞重要的增殖信号，也是乳腺癌内分泌治疗的靶点。本课题组前期系统证实ERα是抑制乳腺癌侵袭转移的重要分子，在乳腺癌侵袭前沿处ERα的丢失促进乳腺癌细胞阿米巴样侵袭转移；但导致肿瘤细胞ERα表达下调的原因不清楚。预实验发现，肿瘤微环境中的脂肪细胞通过外泌体携带miR-148a诱导乳腺癌细胞ERα表达下调，进而对内分泌治疗药物tamoxifen不敏感。本项目拟在前期研究基础上，通过临床标本分析和体内外实验系统阐明在乳腺癌微环境中，脂肪细胞通过外泌体携带miR-148a，抑制乳腺癌细胞中ERα表达，从而促进乳腺癌他莫昔芬耐药。本课题通过肿瘤微环境中脂肪细胞与乳腺癌细胞相互作用的研究，既解释了肿瘤细胞ERα表达下降的机制，又丰富了脂肪细胞在乳腺癌tamoxifen耐药中的作用，为乳腺癌tamoxifen耐药提供新机理，也为解决耐药问题提供新思路。

ERα信号通路是ERα阳性乳腺癌细胞重要的增殖信号，也是乳腺癌内分泌治疗的靶点。本.课题组前期系统证实ERα是抑制乳腺癌侵袭转移的重要分子，在乳腺癌侵袭前沿处ERα的丢失.促进乳腺癌细胞阿米巴样侵袭转移；但导致肿瘤细胞ERα表达下调的原因不清楚。实验发现.，肿瘤微环境中的脂肪细胞通过外泌体携带miR-148a诱导乳腺癌细胞ERα表达下调，进而对内.分泌治疗药物tamoxifen不敏感。本项目在前期研究基础上，通过临床标本分析和体内外实.验系统阐明在乳腺癌微环境中，脂肪细胞通过外泌体携带miR-148a，抑制乳腺癌细胞中ERα表.达，从而促进乳腺癌他莫昔芬耐药。本课题通过肿瘤微环境中脂肪细胞与乳腺癌细胞相互作用.的研究，既解释了肿瘤细胞ERα表达下降的机制，又丰富了脂肪细胞在乳腺癌tamoxifen耐药.中的作用，为乳腺癌tamoxifen耐药提供新机理，也为解决耐药问题提供新思路。