Abstract Resistance to antiestrogen therapy is a major challenge to the treatment of estrogen receptor–positive (ER+) metastatic breast cancer (MBC). While endocrine therapies such as tamoxifen, aromatase inhibitors, and fulvestrant are initially effective, most patients ultimately develop resistance, leading to progressive metastatic disease. Psychosocial stress, widely reported in breast cancer patients, is a clinically relevant factor that worsens outcomes. Elevated chronic levels of norepinephrine (NE), a hallmark of stress physiology, correlate with poor prognosis and increased metastatic burden in breast cancer. We and others have shown the clear negative effect of chronic adrenergic stress in driving immunomodulatory changes that favor tumorigenesis. However, the direct, tumor-intrinsic effects of adrenergic stimulation remain underexplored and not well characterized. Here, we explore a previously unrecognized mechanism by which adrenergic stress drives ER+ breast cancer cells toward a therapy-resistant and metastatic phenotype. We first confirmed that human ER+ breast tumor, and culture murine and human ER+ breast cancer cells, express α2A-, β1-, and β2-adrenergic receptors at both transcript and protein levels using integrated transcriptomic analysis and validated through immunocytochemistry. Functionally, NE promotes proliferation in both estrogen-rich and estrogen-deprived conditions and cooperates with 17β-estradiol (E2) to significantly enhance clonogenicity, anchorage-independent sphere formation, CD44 expression, and migration—features consistent with cellular plasticity and partial cancer stem-like phenotypes. Crucially, we show that NE partially rescues ER+ breast cancer cells from growth inhibition by fulvestrant and tamoxifen, suggesting adrenergic signaling acts as a bypass mechanism that subverts endocrine blockade. We also observe that long-term exposure to NE plus E2 confers persistent cellular changes, as these cells maintain enhanced clonogenic potential even after withdrawal of stimuli. Pharmacologic interrogation using selective adrenergic antagonists abrogates these NE-mediated phenotypes in ER+ breast cancer cells and identifies α2A-adrenergic signaling as a key driver of endocrine resistance. Our findings establish that chronic adrenergic stimulation provides selective pressure on ER+ breast cancer cells and drives therapy-resistance, and transition of cells into stem-like states through tumor-intrinsic mechanisms independent of immune suppression. This work increases the potential role of stress in ER+ breast cancer and supports a new therapeutic paradigm—targeting adrenergic signaling not just to modulate the immune microenvironment, but to directly disrupt tumor plasticity and restore endocrine sensitivity. These insights provide strong rationale for incorporating adrenergic inhibitors into treatment strategies and open the door for potential clinical trials leveraging stress-targeted therapies to overcome therapeutic resistance for patients with endocrine-resistant MBC. Citation Format: G. Gastelum Martinez, M. Rezaei, P. Miller, C. Pine, Y. Anbalagan, N. Bishopric, B. Hudson, M. Lippman. Stress-induced adrenergic signaling promotes endocrine resistance in ER-positive breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-16.
Martinez et al. (Tue,) studied this question.