Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
Department of Orthopedics, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Cancer Sci. 2020 Oct;111(10):3653-3664. doi: 10.1111/cas.14587. Epub 2020 Aug 13.
Cholesterol is a risk factor for breast cancer. However, it is still unclear whether the cholesterol biosynthesis pathway plays any significant role in breast carcinogenesis. 24-Dehydrocholesterol reductase (DHCR24) is a key enzyme in the cholesterol synthesis pathway. Although DHCR24 is reported to have different functions in different cancers, it is not clear whether DHCR24 is involved in breast cancer. In this study, we found that DHCR24 expression was higher in breast cancer especially in luminal and HER2 positive breast cancer tissues compared with normal breast. Changes in DHCR24 expression altered cellular cholesterol content without affecting the adherent growth of breast cancer cells. However, DHCR24 knockdown reduced whereas DHCR24 overexpression enhanced breast cancer stem-like cell populations such as mammosphere and aldehyde dehydrogenase positive cell numbers. In addition, DHCR24 overexpression increased the expression of the Hedgehog pathway-regulated genes. Treating DHCR24 overexpressing breast cancer cell lines with the Hedgehog pathway inhibitor GANT61 blocked DHCR24-induced mammosphere growth and increased mRNA levels of the Hedgehog regulated genes. Furthermore, expression of a constitutively activated mutant of Smoothened, a key hedgehog signal transducer, rescued the decreases in mammosphere growth and Hedgehog regulated gene expression induced by knockdown of DHCR24. These results indicate that DHCR24 promotes the growth of breast cancer stem-like cells in part through enhancing the Hedgehog signaling pathway. Our data suggest that cholesterol contribute to breast carcinogenesis by enhancing Hedgehog signaling and cancer stem-like cell populations. Enzymes including DHCR24 involved in cholesterol biosynthesis should be considered as potential treatment targets for breast cancer.
胆固醇是乳腺癌的一个风险因素。然而，胆固醇生物合成途径是否在乳腺癌发生中发挥重要作用仍不清楚。24-去氢胆固醇还原酶（DHCR24）是胆固醇合成途径中的关键酶。尽管有报道称 DHCR24 在不同的癌症中具有不同的功能，但尚不清楚 DHCR24 是否参与乳腺癌的发生。在本研究中，我们发现与正常乳腺组织相比，DHCR24 在乳腺癌，特别是管腔型和 HER2 阳性乳腺癌组织中的表达更高。DHCR24 表达的改变改变了细胞内胆固醇的含量，但不影响乳腺癌细胞的贴壁生长。然而，DHCR24 敲低减少而 DHCR24 过表达增加了乳腺癌干细胞样细胞群体，如乳腺球体和醛脱氢酶阳性细胞的数量。此外，DHCR24 过表达增加了 Hedgehog 通路调控基因的表达。用 Hedgehog 通路抑制剂 GANT61 处理 DHCR24 过表达的乳腺癌细胞系，阻断了 DHCR24 诱导的乳腺球体生长，并增加了 Hedgehog 调控基因的 mRNA 水平。此外，表达组成型激活的 Smoothened 突变体，一种关键的 Hedgehog 信号转导物，挽救了由 DHCR24 敲低引起的乳腺球体生长和 Hedgehog 调控基因表达的降低。这些结果表明，DHCR24 通过增强 Hedgehog 信号通路促进乳腺癌干细胞样细胞的生长。我们的数据表明，胆固醇通过增强 Hedgehog 信号和癌症干细胞样细胞群体促进乳腺癌的发生。包括 DHCR24 在内的参与胆固醇生物合成的酶应被视为乳腺癌潜在的治疗靶点。
