How loss of tumor suppressor drives ER+ breast cancer to metastasize to the bone

A research team from Baylor College of Medicine has discovered how a loss of tumor suppressor neurofibromin (NF1) in estrogen receptor-positive (ER+) breast cancer contributes to the cancer's tendency to spread to bone. Published in Cancer Letters, the findings reveal that NF1 loss plays a key role in linking therapy resistance with increased bone metastatic potential, suggesting that matching patients' NF1 tumor status with existing therapies could reduce bone metastasis incidence.

ER+ breast cancers account for about 70% of cases, and metastasis causes approximately half a million deaths each year globally. The study, led by Dr. Eric C. Chang, explored how NF1 loss drives ER+ breast cancer cells to preferentially metastasize to bone. NF1 normally acts as a tumor suppressor, controlling cell growth, and its loss can make primary ER+ breast cancer tumors resistant to hormone therapy, aiding growth.

The researchers found that NF1-depleted ER+ breast cancer cells express genes typically active in bone cells and trigger osteoclast activity, leading to excessive bone breakdown and loss. This creates a vicious cycle where damaged bone releases growth factors that stimulate tumor growth. Additionally, NF1 loss weakens the immune system's response to cancer, as tumors with low NF1 levels have fewer active CD8+ T cells and signs of T-cell exhaustion.

Laboratory experiments confirmed that NF1-deficient cancer cells suppress immune T-cell proliferation, reduce immune signaling molecules, and hinder engineered cancer-killing T cells from destroying tumor cells. The findings suggest that NF1 loss allows ER+ breast cancer cells to remodel their environment to favor their survival and growth, promoting bone destruction and suppressing antitumor immunity.

Identifying NF1 status as a potential biomarker could help identify patients at higher risk of bone metastasis, and therapies targeting bone remodeling, immune suppression, or NF1-related pathways might offer new treatment opportunities.