Adrian Lee, Professor at University of Pittsburgh, shared on LinkedIn:
“Six years. That’s how long this paper took from first idea to publication – and it’s finally out in Nature Aging.
‘Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women’ is, at its heart, an attempt to answer a classic paradox in breast cancer: why does ER+ breast cancer become more common with age, even as circulating estrogen drops after menopause? Why do anti-estrogen therapies even work in post-menopausal breast cancer?
Using an aged rat model alongside matched plasma and tumor tissue from patients, we found:
- Older patients have an estrone (E1)-predominant circulating environment, but their tumors locally convert E1 to the more potent estradiol (E2) – largely through age-related increases in the enzyme HSD17B7. Blocking HSD17B7 in patient-derived organoids from older women shut down estrogen signaling and proliferation.
- The aged tumor microenvironment is chemokine-rich (especially CCL2) but paradoxically immune-dysfunctional, driving macrophages toward an immunosuppressive, T-cell-suppressing state.
- Targeting either the estrogen axis (HSD17B7) or the chemokine axis (CCL2), and especially both together, could offer a new, age-specific therapeutic strategy for older women, who are so often underrepresented in breast cancer trials.
None of this happens without the people who lived it. This paper was spearheaded by Neil Carleton, an MD/PhD student in our lab who somehow managed to run a rat carcinogenesis study, wrangle multi-omic human cohorts, build patient-derived organoids, and still write a fantastic paper, all while finishing his doctorate. Neil is now in internal medicine residency at Brigham and Women’s Hospital. Enormously proud of him.
Huge thanks also to my long-time scientific partner Steffi Oesterreich and the entire Women’s Cancer Research Center team, our collaborators, and- most importantly – the patients and donors who made their tissue and time available to us. In particular, we are in debt to the Komen Tissue Bank and the women who donated normal breast tissue and blood for research! Science like this simply doesn’t happen without that generosity.”
Title: Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women
Authors: 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.
Read the full article.
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