科研之友
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摘要
Although antiestrogen therapies are successful in many patients with estrogen receptor alpha-positive (ER alpha(+)) breast cancer, 25% to 40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSC), further investigations have been limited by the paucity of preclinical ER alpha(+) tumor models. Here, we examined a mouse model of prolactin-induced aggressive ER alpha(+) breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ER alpha(+) tumors. Like a subset of ER alpha(+) patient cancers, the prolactin-induced adenocarcinomas contained two major tumor sub-populations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial-mesenchymal transition, and increased double-positive (K8/K5) cells. In primary tumor-sphere cultures, ICI stimulated CSC self-renewal and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ER alpha(+) breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.
Significance: This study suggests that treatment of a subset of ER alpha(+) breast cancers with antiestrogen therapies may not only fail to slow growth but also promote aggressive behavior by evoking tumor cell plasticity and regenerative CSC activity.
- 出版日期2018-4-1
