Farnie Gillian, Johnson Rachael L, Williams Kathryn E, Clarke Robert B, Bundred Nigel J
Cancer Stem Cell Research; University of Manchester; Institute of Cancer Sciences; Manchester Academic Health Science Centre; Paterson Building; The Christie NHS Foundation Trust; Manchester, UK.
Surgical Oncology; University Hospital of South Manchester NHS Foundation Trust; Wythenshawe Hospital; Manchester, UK.
Cell Cycle. 2014;13(3):418-25. doi: 10.4161/cc.27201. Epub 2013 Nov 18.
Breast-conserving surgery for ductal carcinoma in situ (DCIS) is often combined with irradiation, reducing recurrence rates to 20% within 10 years; however, there is no change in overall survival. Evidence in the invasive breast indicates that breast cancer stem cells (CSCs) are radiotherapy-resistant and are capable of re-initiating a tumor recurrence; hence, targeting CSCs in high risk DCIS patient may improve survival. HER2 is overexpressed in 20% of DCIS and is known to be highly active in breast CSCs; we therefore investigated the effect of Lapatinib on DCIS CSC activity using 2 in vitro culture systems. Two DCIS cell lines DCIS.com (HER2 normal) and SUM225 (HER2 overexpressed) as well as DCIS cells from patient samples (n = 18) were cultured as mammospheres to assess CSC activity and in differentiated 3D-matrigel culture to determine effects within the non-CSCs. Mammosphere formation was reduced regardless of HER2 status, although this was more marked within the HER2-positive samples. When grown as differentiated DCIS acini in 3D-matrigel culture, Lapatinib only reduced acini size in the HER2-positive samples via decreased proliferation. Further investigation revealed lapatinib did not reduce self-renewal activity in the CSC population, but their proliferation was decreased regardless of HER2 status. In conclusion we show Lapatinib can reduce DCIS CSC activity, suggesting that the use of Lapatinib in high-risk DCIS patients has the potential to reduce recurrence and the progression of DCIS to invasive disease.
导管原位癌（DCIS）的保乳手术通常与放疗相结合，可将10年内的复发率降低至20%；然而，总体生存率并无变化。浸润性乳腺癌的证据表明，乳腺癌干细胞（CSCs）对放疗具有抗性，并且能够重新引发肿瘤复发；因此，针对高危DCIS患者的CSCs可能会提高生存率。20%的DCIS中HER2过表达，并且已知其在乳腺CSCs中高度活跃；因此，我们使用两种体外培养系统研究了拉帕替尼对DCIS CSC活性的影响。将两种DCIS细胞系DCIS.com（HER2正常）和SUM225（HER2过表达）以及来自患者样本的DCIS细胞（n = 18）培养成乳腺球以评估CSC活性，并在分化的三维基质胶培养中确定对非CSCs的影响。无论HER2状态如何，乳腺球形成均减少，尽管在HER2阳性样本中更为明显。当在三维基质胶培养中生长为分化的DCIS腺泡时，拉帕替尼仅通过降低增殖减少HER2阳性样本中的腺泡大小。进一步研究表明，拉帕替尼并未降低CSC群体中的自我更新活性，但无论HER2状态如何，其增殖均降低。总之，我们表明拉帕替尼可降低DCIS CSC活性，这表明在高危DCIS患者中使用拉帕替尼有可能降低复发率以及DCIS进展为浸润性疾病的可能性。
