Targeting a Novel ER/HOXB7 Signaling Loop in Tamoxifen-Resistant Breast Cancer

摘要

Summary: The majority of patients with breast cancer present with an estrogen receptor-positive (ER+) tumor, and the endocrine agent tamoxifen is a mainstay for their treatment. Unfortunately, however, resistance remains a major problem because most patients who respond eventually have a recurrence. Thus, an enduring challenge in the breast cancer field is to identify mechanisms underlying tamoxifen resistance. Jin and colleagues describe a novel ER/HOXB7 signaling loop in tamoxifen-resistant breast cancer models. Importantly, they reveal that targeting this signaling loop has great promise as an approach to treat patients with tamoxifen-resistant breast cancer. The approximately 70% of breast cancer patients whose tumors are estrogen receptor-positive (ER+) are treated with endocrine agents, including tamoxifen, the first clinically successful ER modulator (SERM), and the more recently introduced agents fulvestrant, an ER degrader (SERD), and aromatase inhibitors that block estradiol production. Endocrine agents have increased the survival of hundreds of thousands of breast cancer patients since the introduction of tamoxifen into the clinic in the mid-1970s (1). Unfortunately, tumor recurrence caused by acquired resistance often occurs (reviewed in refs. 2 and 3). Therefore, it is crucial to gain an understanding of the mechanisms underlying endocrine therapy resistance. ER biology is quite complex, and it is likely that multiple, nonexclusive mechanisms contribute to endocrine resistance. For example, loss of ER, which is observed in 15% to 20% of recurrences, is an obvious resistance mechanism (4). Receptor tyrosine kinase (RTK) overexpression has also been proposed to contribute to endocrine resistance. Indeed, breast tumors with high expression and activity of EGFRand ERBB2 are less sensitive to tamoxifen (5). Moreover, the subgroup of patients with breast cancer with ER+ tumors and the ERBB2 amplicon generally do not respond to tamoxifen (6). These clinical data suggest that ERBB RTK signaling can circumvent the requirement for ER signaling.