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
5 min
Abstract Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. The peak incidence of diagnosis occurs around age 70, even though these post-menopausal patients have low circulating levels of estradiol (E2). Despite the hormone sensitivity of age-related tumors, we have a limited understanding of the interplay between systemic and local hormones, chronic inflammation, and immune changes that contribute to the growth and development of these tumors. Here, we show that aged F344 rats treated with the dimethylbenz(a)anthracene / medroxyprogestrone acetate (DMBA/MPA) carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment promotes tumor initiation and impacts growth. Single-nuclei RNA-seq (snRNA-seq) of the tumors showed broad local immune dysfunction that was associated with circulating chronic inflammation. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with an estrone (E1)-predominant estrogen disposition in the systemic circulation, tumors in older patients increase HSD17B7 expression to convert E1 to E2 in the tumor microenvironment (TME) and have local E2 levels similar to pre-menopausal patients. Concurrently, trackable increases in several chemokines, defined most notably by CCL2, promote a chronically inflamed but immune dysfunctional TME. This unique milieu in the aged TME, characterized by high local E2 and chemokine-enriched chronic inflammation, promotes both accumulation of tumor-associated macrophages (TAMs), which serve as signaling hubs, as well as polarization of TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. Pharmacologic targeting of estrogen signaling (either by HSD17B7 inhibition or with fulvestrant) and chemokine inflammation both decrease local E2 and prevent macrophage polarization. Overall, these findings suggest that chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth and offer potential therapeutic insight to treat these patients. Translational Summary We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity. Graphical Abstract
Breast cancer, particularly the estrogen receptor-positive (ER+) subtype, is strongly associated with aging. Despite lower systemic estradiol (E2) levels in postmenopausal women, the incidence of ER+ breast cancer remains high. This study investigates how the systemic and local hormonal and inflammatory environment in older women contributes to a tumor-permissive microenvironment.
The researchers integrated multiple models and datasets to characterize the aged breast tumor microenvironment (TME). They utilized an aged F344 rat model to study tumor development, analyzed matched plasma and tissue samples from a large cohort of ER+/HER2- breast cancer patients and age-matched donors, and employed patient-derived organoids (PDOs) to test the functional impact of estrogen metabolism and inflammation on macrophage polarization.
The study reveals that while systemic circulation in older patients is dominated by estrone (E1), the local breast TME maintains high levels of E2. This is driven by an age-related increase in the expression of the enzyme HSD17B7, which converts E1 to E2 within the tumor. Furthermore, the aged TME is characterized by chronic, chemokine-enriched inflammation—most notably elevated CCL2—which promotes the accumulation and polarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CD206+/PD-L1+ phenotype. Pharmacological inhibition of HSD17B7 or the CCL2 axis was shown to reduce E2 conversion and dampen the immunosuppressive macrophage response, suggesting these pathways are potential therapeutic targets for older patients.
These findings provide a mechanistic link between systemic aging, local hormone metabolism, and immune dysfunction in ER+ breast cancer. By identifying HSD17B7 and chemokine signaling as key drivers of the tumor-permissive environment in older women, this research highlights potential avenues for developing age-specific therapeutic strategies that could improve outcomes while potentially reducing the reliance on systemic endocrine therapies.
Alex: Did they test whether disrupting both pathways together has a different effect than either alone?
Sam: They did, and this is where the therapeutic framing becomes more concrete. Targeting both HSD17B7 and the CCL2-driven chemokine axis together helped reverse the immunosuppressive macrophage polarization more effectively than either intervention alone. The paper frames this as a rationale for combination regimens — hitting the metabolic refinery and the immune microenvironment simultaneously.
Alex: That's an appealing therapeutic logic. But what's the honest constraint on how much weight we can put on it?
Sam: A few things. The correlation between HSD17B7 expression levels and the intratumoral estradiol-to-estrone ratio, while present, was modest — which means the enzyme is a meaningful contributor but not the sole determinant. Other factors are clearly in play. More fundamentally, the causal evidence is still ex vivo. We have organoid data and animal models, but no longitudinal in vivo evidence that this pathway is necessary for progression in patients. And aging itself is deeply heterogeneous — the biological age of a tumor microenvironment doesn't map cleanly onto chronological age, which complicates any age-stratified therapeutic strategy.
Alex: So the picture is: a well-supported mechanism, a plausible therapeutic target, but the clinical translation still needs prospective validation.
Sam: That's a fair read. What the paper does establish is a coherent framework — local estrogen synthesis via HSD17B7, reinforced by an inflammaging-driven immune microenvironment — that could explain why ER-positive tumors remain active in a low-estrogen systemic context. Whether that framework survives contact with clinical trial data is the open question. But it's a meaningful step toward age-aware oncology, where treatment strategy accounts for the biology of the aged tumor microenvironment rather than treating all ER-positive disease as equivalent.
Alex: That reframing alone seems worth paying attention to. Thanks for walking through the mechanism, Sam. And thanks to everyone listening — this has been ResearchPod.