Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, 27151, USA.
Department of Medical Microbiology, Immunology & Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Breast Cancer Res Treat. 2019 May;175(1):77-90. doi: 10.1007/s10549-018-05126-3. Epub 2019 Feb 6.
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer which could progress to or recur as invasive breast cancer. The underlying molecular mechanism of DCIS progression is yet poorly understood, and appropriate biomarkers to distinguish benign form of DCIS from potentially invasive tumor are urgently needed.
To identify the key regulators of DCIS progression, we performed gene-expression analysis of syngeneic breast cancer cell lines MCF10A, DCIS.com, and MCF10CA and cross-referenced the targets with patient cohort data.
We identified ID2 as a critical gene for DCIS initiation and found that ID2 promoted DCIS formation by enhancing cancer stemness of pre-malignant cells. ID2 also plays a pivotal role in survival of the aggressive cancer cells. In addition, we identified INHBA and GJB2 as key regulators for the transition of benign DCIS to aggressive phenotype. These two genes regulate migration, colonization, and stemness of invasive cancer cells. Upregulation of ID2 and GJB2 predicts poor prognosis after breast-conserving surgery. Finally, we found a natural compound Helichrysetin as ID2 inhibitor which suppresses DCIS formation in vitro and in vivo.
Our results indicate that ID2 is a key driver of DCIS formation and therefore is considered to be a potential target for prevention of DCIS, while INHBA and GJB2 play vital roles in progression of DCIS to IDC and they may serve as potential prognosis markers.
导管原位癌（DCIS）是一种非浸润性乳腺癌，可能进展为或复发为浸润性乳腺癌。DCIS 进展的潜在分子机制尚不清楚，急需合适的生物标志物将良性 DCIS 与潜在侵袭性肿瘤区分开来。
为了鉴定 DCIS 进展的关键调控因子，我们对同源乳腺癌细胞系 MCF10A、DCIS.com 和 MCF10CA 进行了基因表达分析，并与患者队列数据进行了交叉参考。
我们确定 ID2 是 DCIS 起始的关键基因，并发现 ID2 通过增强前恶性细胞的癌症干细胞特性促进 DCIS 形成。ID2 还在侵袭性癌细胞的存活中发挥关键作用。此外，我们还确定了 INHBA 和 GJB2 是良性 DCIS 向侵袭性表型转化的关键调控因子。这两个基因调节侵袭性癌细胞的迁移、定植和干细胞特性。ID2 和 GJB2 的上调预示着保乳手术后的预后不良。最后，我们发现了一种天然化合物 Helichrysetin，它是 ID2 的抑制剂，可抑制体外和体内的 DCIS 形成。
我们的研究结果表明，ID2 是 DCIS 形成的关键驱动因素，因此被认为是预防 DCIS 的潜在靶点，而 INHBA 和 GJB2 在 DCIS 向 IDC 进展中起着至关重要的作用，它们可能作为潜在的预后标志物。
