Matched ER+/ER− breast cancer models reveal disparate estrogen effects in mammary and pulmonary premetastatic environments

Estrogen targets multiple cell types that impact tumor progression. However, effects on metastatic processes and interplay of signals to cancer cells and stromal cells are poorly understood. Using an immunocompetent preclinical model of estrogen receptor alpha (ER + ) breast cancer and two matched CRISPR-Cas9 Esr1 -ablated (ER-) cell lines, we demonstrate that supplemental 17β-estradiol fosters a pro-tumor immune environment for both ER+ and ER- mammary tumors, but exerts disparate effects on early pulmonary colonization following intravenous injection: promoting ER + , but inhibiting ER- tumor lesions. Interrogation of mammary tumor environments and splenic and pulmonary immune cells revealed marked effects of 17β-estradiol on immune subpopulations and activity. RNASeq analyses illuminated the potential of ER+ tumor cells for immune evasion, revealing a new facet of estrogen action in ER+ cancer. This context-specific interplay among estrogen responsive cells in the mammary and premetastatic pulmonary environments has implications beyond breast cancers, including ER- cancers of varying origins.