Breast cancer is a significant cause of morbidity and mortality in women, with over two million new cases reported worldwide each year, the majority of which occur in post-menopausal women. Despite advances in early detection and treatment, approximately one-third of patients diagnosed with breast cancer will develop metastatic disease. The pathogenesis and progression of breast cancer are influenced by a variety of biological and social risk factors, including age, ethnicity, pregnancy status, diet, and genomic alterations. Recent advancements in breast cancer research have focused on harnessing the power of the patient’s adaptive and innate immune systems for diagnostic and therapeutic purposes. The breast immune microenvironment plays a critical role in regulating tissue homeostasis and resistance to tumorigenesis. In this review, we explore the dynamic changes in the breast immune microenvironment that occur with age, how these changes impact breast cancer development and progression, and how targeted therapeutic interventions that leverage the immune system can be used to improve patient outcomes. Our review emphasizes the importance of understanding the complex interplay between aging, the immune system, and breast cancer, and highlights the potential of immune-based therapies in the fight against this devastating disease.

Background: The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC (PPBC) subtype, identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. Methods: We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women aged ≤40 years included in the Young Women’s Breast Cancer Study. We analyzed data using univariable linear regression and multivariable sliced inverse regression to account for higher order interactions among biomarkers. Results: In keratin-rich segments, progesterone receptor (PR) (P = 1.00 × 10−4) and PTEN (P = 1.00 × 10−3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (P = 4.00 × 10−4), SMA (P = 1.00 × 10−4), and NF-1 (P = 1.00 × 10−3). In keratin-poor segments, univariable significant positive associations were found for PR (P = 2.00 × 10−4) and PTEN (P = 1.00 × 10−3), whereas CD20 (P = 3.00 × 10−4) and CTLA4 (P = 4.00 × 10−5) were negatively associated; multivariable significant associations were found for fibronectin (P = 3.00 × 10−5) and pan-Akt (P = 1.00 × 10−3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN, and CD20 were strongest among women with the shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA, and CTLA4 replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T-cell exhaustion signature previously linked to poor prognosis among premenopausal women. Conclusion: These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.

Benign breast disease (BBD) is common and confers heterogeneous increases in breast cancer risk; however, risk prediction relies mainly on histopathology a

Basal-like/triple-negative breast cancers occur disproportionately at younger ages among non-Hispanic Black women (NHBW), but whether normal breast epithelium shows measurable, reversible differences in proliferative signaling is unclear. Histologically normal lobules from parity-, age-, and body mass index-matched NHBW and non-Hispanic White women (NHWW) donors (10 versus 10) were profiled using targeted transcriptomics (IO360/BC360) and whole-slide quantitative immunohistochemistry for epidermal growth factor receptor (EGFR), KIT, and cytokeratin-5. Eighty-nine transcripts differed between groups at false discovery rate < 0.10, with EGFR and KIT elevated in NHBW lobules and enrichment of basal/receptor tyrosine kinase-linked programs. Quantitative immunohistochemistry confirmed higher protein in NHBW tissue; in lobule-level models, the group effect (NHBW - NHWW) was EGFR β = 0.055, P = 0.010; KIT β = 0.093, P = 0.0027; and cytokeratin-5 β = 0.126, P = 0.027. In prestasis human mammary epithelial cells, 24-hour treatment with EGFR (lapatinib) or KIT (ripretinib) inhibitors increased cyclin-dependent kinase inhibitors, decreased cyclins/cyclin-dependent kinase 4/6, and enforced G₁ arrest; EGFR inhibition also increased apoptosis. Together, these data identify a coordinated EGFR/KIT-linked proliferative bias in NHBW epithelium that is rapidly reversible in vitro, supporting validation in larger cohorts and pharmacodynamic window studies.