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<p>Estrogen receptor-positive (ER<sup>+</sup>) breast cancer is the most common subtype of breast cancer and is an age-related disease. How systemic and tumor microenvironment hormone signaling intersects with chronic inflammation and how this shapes aging-associated tumor biology remain incompletely understood. Here, using an aged rat model of ER<sup>+</sup> tumors, we identify age-associated differences in tumor development and immune features. In parallel, analysis of samples from patients with ER<sup>+</sup>/HER2<sup>−</sup> breast cancer and age-matched controls demonstrated estrone-predominant systemic estrogen patterns and increased tumor HSD17B7 expression in older patients, consistent with enhanced local estrone-to-estradiol conversion. In patient-derived organoids from older women, pharmacologic inhibition of HSD17B7 reduced estrogen conversion and proliferation-associated transcriptional programs. Tumors from older patients also exhibited chemokine enrichment, including CCL2, associated with immunosuppressive macrophage features. Targeting both estrogen signaling and chemokine pathways attenuated macrophage polarization ex vivo. These findings support a model linking age-associated hormonal and inflammatory changes to features of a tumor-permissive microenvironment in ER<sup>+</sup> breast cancer.</p>

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Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Neil Carleton,
  • Alexander Chih-Chieh Chang,
  • Sanghoon Lee,
  • Ruxuan Li,
  • Jian Zou,
  • Daniel D. Brown,
  • Jagmohan Hooda,
  • Jian Chen,
  • Rahul Kumar,
  • Linda R. Klei,
  • Lora H. Rigatti,
  • Joseph Newsome,
  • Dixcy Jaba Sheeba John Mary,
  • Jennifer M. Atkinson,
  • Raymond E. West III,
  • Thomas D. Nolin,
  • Patrick J. Oberly,
  • Ziyu Huang,
  • Donald Poirier,
  • Emilia J. Diego,
  • Peter C. Lucas,
  • George C. Tseng,
  • Michael T. Lotze,
  • Priscilla F. McAuliffe,
  • Ioannis K. Zervantonakis,
  • Steffi Oesterreich,
  • Adrian V. Lee

摘要

Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. How systemic and tumor microenvironment hormone signaling intersects with chronic inflammation and how this shapes aging-associated tumor biology remain incompletely understood. Here, using an aged rat model of ER+ tumors, we identify age-associated differences in tumor development and immune features. In parallel, analysis of samples from patients with ER+/HER2− breast cancer and age-matched controls demonstrated estrone-predominant systemic estrogen patterns and increased tumor HSD17B7 expression in older patients, consistent with enhanced local estrone-to-estradiol conversion. In patient-derived organoids from older women, pharmacologic inhibition of HSD17B7 reduced estrogen conversion and proliferation-associated transcriptional programs. Tumors from older patients also exhibited chemokine enrichment, including CCL2, associated with immunosuppressive macrophage features. Targeting both estrogen signaling and chemokine pathways attenuated macrophage polarization ex vivo. These findings support a model linking age-associated hormonal and inflammatory changes to features of a tumor-permissive microenvironment in ER+ breast cancer.