A novel function of prolactin signaling in brain metastasis in HER2-positive breast cancer

About This Grant

PROJECT SUMMARY Brain metastases develop in over half of patients with HER2-positive (HER2.) breast cancer and remain a major cause of mortality despite advances in HER2-targeted therapies. The long-term goal of this project is to elucidate and therapeutically target mechanisms that enable HER2. breast cancer cells to colonize and thrive in the brain. Using newly developed immunocompetent mouse models that reproducibly form HER2. breast cancer brain metastases, our studies uncovered a previously unrecognized tumor–pituitary–prolactin axis that drives metastatic progression through systemic neuroendocrine regulation. Transcriptomic profiling revealed that while HER2+ breast cancer brain-metastatic cancer cells lack estrogen and progesterone receptors, they are enriched in prolactin receptor (PRLR) signaling. Strikingly, PRLR depletion in HER2+ breast cancer models markedly reduced brain-metastatic growth without affecting the primary tumor, establishing prolactin signaling as a selective driver of brain metastasis. Mechanistically, we found that prolactin activates a noncanonical PRLR–SRC–p70S6K pathway in the cancer cells to promote cancer cell proliferation in the brain. We also found that i) prolactin release from the pituitary gland is stimulated by cancer-cell secretion of oxytocin and ii) anterior pituitaries from tumor-bearing mice exhibit reduced CREB1 activity and dopamine D2 receptor expression, which leads to a disruption of dopamine-mediated inhibition of prolactin release. These two tumor-induced aberrantly regulated neuroendocrine pathways cause a sustained elevation of plasma prolactin. Mouse models are essential for the proposed metastasis studies because these systemic mechanisms require an intact, species-matched physiological system that includes pituitary hormone regulation, an intact immune system, and the target tissue microenvironment of the brain. Our findings therefore define a feed-forward circuit in which metastatic tumors hijack central neuroendocrine control to sustain prolactin signaling and promote brain metastasis. Aim 1 of this proposal will define how prolactin drives HER2. brain metastasis through PRLRdependent, noncanonical p70S6K signaling and establish its clinical relevance in patient-derived metastases. Aim 2 will investigate the mechanisms by which tumors elevate systemic prolactin through oxytocin secretion and CREB1-mediated suppression of dopamine feedback and will test pharmacologic strategies to interrupt this axis and block metastatic growth. This work is innovative because it identifies a previously unrecognized tumor–pituitary feedback loop that sustains brain metastasis, integrating tumor-intrinsic signaling with systemic endocrine regulation. It is significant because it reveals prolactin signaling as a targetable vulnerability in HER2. brain metastasis and introduces systemic hormonal modulation as a new therapeutic approach to prevent or treat metastatic progression in these patients.