Uncoupling protein 1 (UCP1) has been implicated in ameliorating metabolic related disorders, of which most symptoms are risk factors for breast cancer. Here, we found that UCP1 was obviously downregulated in basal-like breast cancer (BLBC) and was positively correlated with improved survival. However, the underlying regulatory mechanisms remain largely unknown. Our studies showed that UCP1 inhibited tumor progression via suppressing aldehyde dehydrogenase (ALDH)-positive breast cancer stem cell (BCSC) population in BLBC. Furthermore, we found that UCP1 induced the upregulation of fructose bisphosphatase 1 (FBP1) which was previously blocked by Snail overexpression, and UCP1 decreased ALDH-positive BCSCs via FBP1-dependent metabolic rewiring, which could be reversed by Snail overexpression. In addition, breast cancer cells co-cultured with UCP1-deficient adipocytes had increased proportion of ALDH-positive BCSCs, indicating a potential protection role of UCP1 in tumor microenvironment. These results suggested that UCP1 suppressed BCSCs through inhibiting Snail-mediated repression of FBP1, and that upregulation of UCP1 might be a previously undescribed therapeutic strategy for combating breast cancer.

Graphical abstract

解偶联蛋白 1 (UCP1) 与改善代谢相关疾病有关，其中大多数症状是乳腺癌的危险因素。在这里，我们发现 UCP1 在基底样乳腺癌 (BLBC) 中明显下调，并且与生存率提高呈正相关。然而，潜在的调控机制在很大程度上仍然未知。我们的研究表明，UCP1 通过抑制 BLBC 中醛脱氢酶 (ALDH) 阳性乳腺癌干细胞 (BCSC) 群来抑制肿瘤进展。此外，我们发现 UCP1 诱导果糖双磷酸酶 1 (FBP1) 的上调，该上调先前被 Snail 过表达阻断，并且 UCP1 通过 FBP1 依赖性代谢重组减少 ALDH 阳性 BCSC，这可以通过 Snail 过表达逆转。此外，与 UCP1 缺陷脂肪细胞共培养的乳腺癌细胞增加了 ALDH 阳性 BCSC 的比例，表明 UCP1 在肿瘤微环境中具有潜在的保护作用。这些结果表明 UCP1 通过抑制 Snail 介导的 FBP1 抑制来抑制 BCSC，并且 UCP1 的上调可能是以前未描述的抗击乳腺癌的治疗策略。

图形概要