Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
School of Basic Medical Sciences, Chengdu University, Chengdu, China.
FASEB J. 2023 Apr;37(4):e22837. doi: 10.1096/fj.202201801R.
Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide. Cancer-associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF-related markers (FSP1, α-SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency-mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the -1968/-1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF-β stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.
乳腺癌是全球女性最常见的恶性肿瘤，也是癌症相关死亡的主要原因。癌症相关成纤维细胞（CAFs）是肿瘤微环境的基本细胞成分之一，在乳腺癌的发生、发展和治疗耐药中起着关键作用。然而，CAFs 从正常成纤维细胞（NFs）激活的详细分子机制仍不清楚。在本研究中，我们报道乳腺癌细胞中的 ZNF32 表达与基质成纤维细胞中 CAF 相关标志物（FSP1、α-SMA 和 FAP）呈负相关，并且缺失 ZNF32 促进 CAFs 的激活，这表现为 CAFs 的增殖和收缩能力增强。ZNF32 缺陷介导的成纤维细胞激活促进了乳腺癌细胞在体外和体内的生长和转移。从机制上讲，我们证明 ZNF32 通过直接结合 TGFB1 启动子的-1968/-1962 区域抑制 TGFB1 转录，从而阻止成纤维细胞的激活。总之，我们的研究结果揭示了 ZNF32 抑制增加乳腺癌细胞中 TGFB1 基因转录的重要机制，随后，高水平的分泌性 TGF-β 刺激 NFs 向 CAFs 的转化，进而促进乳腺癌的恶性进展。我们的数据表明 ZNF32 是一种针对乳腺癌的潜在治疗策略。
