Panoply™ Human ERBB2 Knockdown Stable Cell Line

The mechanisms of acquired endocrine resistance and advanced recurrence in ER+/HER2− breast cancer patients are complex and not fully elucidated. Here, researchers evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. The researchers found that the expression pattern of FOXM1 changed from ERα-dependent to HER2-dependent and ERα-independent, which may allow disseminated ER+/HER2− cells to restart tumor cell growth and metastasis under endocrine therapy. In the presence of ERα inhibitors, the NF-κB signaling pathway maintained the expression of HER2 and FOXM1 in CTCs, suggesting that NF-κB and FOXM1 may be effective targets for preventing advanced recurrence and treating endocrine resistance. These data collectively demonstrate that CTCs from endocrine-resistant patients can elucidate the mechanisms of acquired endocrine resistance and can be used to test potential drug strategies to combat resistance.

HER2 is involved in the development of endocrine resistance, and breast cancer patients with HER2 amplification have limited responses to endocrine therapy. To investigate the potential role of HER2 in the resistance of CTC-ITB-01 cells to ERα inhibitors and in regulating FOXM1 expression, researchers constructed HER2-stably knockdown CTC-ITB-01 and MCF7 cells. In HER2-knockdown CTC-ITB-01 cells, FOXM1 expression was significantly reduced, cell death was increased (manifested as increased cleavage of poly(ADP-ribose) polymerase-1 (PARP1) and caspase-7), and colony-forming ability was significantly reduced (Figure 1A). In HER2-knockdown MCF7 cells, FOXM1 expression was not reduced, and no cleavage of PARP1 and caspase-7 was observed (Figure 1B, upper panel). Furthermore, no significant decrease in colony-forming ability was detected after HER2 knockdown in MCF7 cells (Figure 1B, lower panel). These results indicate that in CTC-ITB-01 cells, FOXM1 expression, cell growth, and survival depend on HER2, while in MCF7 cells, FOXM1 expression depends on ERα rather than HER2. Interestingly, both HER2 knockdown cell lines showed increased ERα expression. These observations suggest an interaction between HER2 and ERα in both cell lines.

Figure 1. Knockdown experiments reveal a role for HER2 in FOXM1 expression, growth and survival in CTC-ITB-01 cells. (Roßwag S, et al., 2021)