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Background Molecular breast imaging (MBI) has shown utility as a supplement to mammography in women with dense breasts. Background parenchymal uptake (BPU), which describes the level of Tc-99 m sestamibi in fibroglandular tissue on MBI, varies among women with similar density. Higher BPU is associated with greater breast cancer risk. The goal of this work is to investigate the histological correlations of BPU that may explain this association with risk. Methods In healthy women with dense tissue on mammography, we prospectively biopsied regions of fibroglandular tissue exhibiting one of the extreme categories of BPU on MBI: either photopenic or marked. Tissue composition of specimens was assessed by measuring area of epithelium, stroma, and fat and counting lobules. Lobular involution status was assessed by an expert pathologist as either none, partial, or complete. Ki-67 index and estrogen receptor-alpha expression were also assessed. Histologic features of photopenic and marked specimens were compared. Results Biopsies were performed in 48 women (mean age 54.9 years [SD 11.1 years]), including 20 with marked BPU and 28 with photopenic BPU. Women with marked BPU were younger (mean age 49.9 vs. 58.4 years, p  = 0.004), had higher body mass index ( p  = 0.01), and were more likely premenopausal ( p  = 0.005). Marked BPU specimens had a higher proportion of epithelium (14.5% vs. 2.2%, p  < 0.001), lower stromal content (44.8% vs. 84.2%, p  = 0.005), similar fat (18.9% vs. 12.9%, p  = 0.41), and greater lobule counts (15.5 vs. 6.3, p  < 0.001) compared to photopenic specimens. Complete lobular involution was less frequent in marked tissue than in photopenic tissue (10.5% vs. 76%, p  < 0.001). Ki-67 index was higher in marked BPU tissues (5.4% vs. 1.6%, p  = 0.006), though the difference was attenuated after adjustment for epithelial area ( p  = 0.26). Estrogen receptor-alpha expression did not differ between marked and photopenic groups (25.6% vs. 28.4%, p  = 0.12). Conclusions Marked BPU on MBI is associated with greater epithelial content, less lobular involution, and higher proliferative activity—features characteristic of tissue at elevated risk for malignant transformation. These findings suggest that BPU provides functional information beyond mammographic density, supporting its role as an imaging biomarker for breast cancer risk in women with dense breasts. Trial registration NCT01240278 || 11/15/2010 and NCT01588834 || 05/01/2012.

The mammary gland undergoes significant changes throughout a woman’s life; from embryonic development to transformations after breastfeeding and during aging. These processes, while essential for normal breast physiology, can increase breast cancer risk when disrupted. This review explores three critical stages: embryonic development; postlactational involution; and age-related lobular involution (ARLI). We highlight key signaling pathways—Wnt, FGF, SHH, Notch, EGFR, and BMP—that guide embryonic development and discuss how their dysregulation can contribute to abnormal growth. For postlactational involution, we examine the two-phase process of cell death and tissue remodeling, showing how disruptions during this period, particularly postpartum, may foster a tumor-promoting environment. We also delve into ARLI and the role of cellular senescence in the aging mammary gland, focusing on the senescence-associated secretory phenotype (SASP) and its impact on inflammation and tissue remodeling. Understanding these processes provides new opportunities for breast cancer prevention and treatment strategies

Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm 2 , median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0–10; 11–20; 21–30; 31–50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96–6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13–7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03–11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40–10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US.

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.

Age-related lobular involution (LI) is a physiological process in which the terminal duct lobular units of the breast regress as a woman ages. Analyses of breast biopsies from women with benign breast disease (BBD) have found that extent of LI is negatively associated with subsequent breast cancer development. Here we assess the natural course of LI within individual women, and the impact of progressive LI on breast cancer risk. The Mayo Clinic BBD cohort consists of 13,455 women with BBD from 1967 to 2001. The BBD cohort includes 1115 women who had multiple benign biopsies, 106 of whom had developed breast cancer. Within this multiple biopsy cohort, the progression of the LI process was examined by age at initial biopsy and time between biopsies. The relationship between LI progression and breast cancer risk was assessed using standardized incidence ratios and by Cox proportional hazards analysis. Women who had multiple biopsies were younger age and had a slightly higher family history of breast cancer as compared with the overall BBD cohort. Extent of LI at subsequent biopsy was greater with increasing time between biopsies and for women age 55 + at initial biopsy. Among women with multiple biopsies, there was a significant association of higher breast cancer risk among those with involution stasis (lack of progression, HR 1.63) as compared with those with involution progression, p  = 0.036. The multiple biopsy BBD cohort allows for a longitudinal study of the natural progression of LI. The majority of women in the multiple biopsy cohort showed progression of LI status between benign biopsies, and extent of progression was highest for women who were in the perimenopausal age range at initial biopsy. Progression of LI status between initial and subsequent biopsy was associated with decreased breast cancer risk.

As a downregulator of the Wnt signaling pathway, SFRP1 is involved in several components of the age-related lobular involution process such as inflammation, apoptosis, and adipogenesis. Because microcalcifications are associated with inflammation, we aimed to demystify the cross talk between SFRP1, inflammatory markers, and microcalcifications by assessing SFRP1 expression (immunohistochemistry) in a cohort of 162 women with different degrees of lobular involution. SFRP1 expression was inversely associated with the degree of lobular involution (OR = 0.84; p-value < 0.01). SFRP1 expression, age at mastectomy, and waist circumference taken together predicted the degree of lobular involution (AUC = 78.1). This predictive model was best in patients with microcalcifications (AUC = 81.1) and in parous women (AUC = 87.8). SFRP1 expression was correlated with leptin (rho = 0.32), TNF-α (rho = 0.21), and IL-6 (rho = 0.21) expression by epithelial cells (all p-values <0.001). SFRP1 expression was lower in nulliparous women with involuted breast tissue compared with parous women with involuted breast tissue (Δmean = −2.31; p-value < 0.01) and was higher in nulliparous women with microcalcifications compared with nulliparous women without microcalcifications (Δmean = 2.4; p-value < 0.05). In this study, we highlighted two SFRP1-based predictive models for incomplete lobular involution and the development of microcalcifications and identified two distinct inflammatory profiles associated with age-related lobular involution in parous and nulliparous women.

A human transcriptome array on ERα-positive breast cancer continuum of risk identified Secreted Frizzled-Related Protein 1 (SFRP1) as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of SFRP1 in breast carcinogenesis remains, nevertheless, not well understood. In this study, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, in the presence of estradiol (E2) and/or hydroxyapatite microcalcifications (HA). Furthermore, we have modulated SFRP1 expression in breast cancer cell lines, including the MCF10A series, and investigated their tumoral properties. We observed that organoids obtained from multiparous mice were resistant to E2 treatment, while organoids obtained from nulliparous mice developed the luminal phenotype associated with a lower ratio between Sfrp1 and Esr1 expression. The decrease in SFRP1 expression in MCF10A and MCF10AT1 cell lines increased their tumorigenic properties in vitro. On the other hand, the overexpression of SFRP1 in MCF10DCIS, MCF10CA1a, and MCF7 reduced their aggressiveness. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis.

Postlactational involution is the process following weaning during which the mammary gland undergoes massive cell death and tissue remodeling as it returns to the pre-pregnant state. Lobular involution is the process by which the breast epithelial tissue is gradually lost with aging of the mammary gland. While postlactational involution and lobular involution are distinct processes, recent studies have indicated that both are related to breast cancer development. Experiments using a variety of rodent models, as well as observations in human populations, suggest that deregulation of postlactational involution may act to facilitate tumor formation. By contrast, new human studies show that completion of lobular involution protects against subsequent breast cancer incidence.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p  < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure ( p  < 0.05), seven SNPs (rs466639: RXRG ; rs2243803: SLC14A2 ; rs2292573: GAB2 ; rs6438424: 3q13.32 ; rs7606918: METAP1D ; rs11668344: TMEM150B ; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution. Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the literature. Indeed, the lack of SFRP1 is associated with both tumor development and patient prognosis. Considering the increased risk of breast tumor development associated with incomplete mammary gland involution, it is crucial to demystify the “grey zone” between physiological age-related involution and tumorigenesis. In this review, we explore the functions of SFRP1 involved in the breast involution processes to understand the perturbations driven by the disappearance of SFRP1 in mammary tissue. Moreover, we question the presence of recurrent microcalcifications identified by mammography. In bone metastases from prostate primary tumor, overexpression of SFRP1 results in an osteolytic response of the tumor cells. Hence, we explore the hypothesis of an osteoblastic differentiation of mammary cells induced by the lack of SFRP1 during lobular involution, resulting in a new accumulation of hydroxyapatite crystals in the breast tissue.