Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization.

Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.

Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model.

Young women have increased risk of vitamin D deficiency, which may increase breast cancer incidence. Here, we assessed the anti-cancer efficacy of vitamin D in mouse models of young-onset breast cancer. In never-pregnant mice, vitamin D supplementation increased serum 25(OH)D and hepatic 1,25(OH)2D3, reduced tumor size, and associated with anti-tumor immunity. These anti-tumor effects were not replicated in a mouse model of postpartum breast cancer, where hepatic metabolism of vitamin D was suppressed post-wean, which resulted in deficient serum 25(OH)D and reduced hepatic 1,25(OH)2D3. Treatment with active 1,25(OH)2D3 induced hypercalcemia exclusively in post-wean mice, highlighting metabolic imbalance post-wean. RNAseq revealed suppressed CYP450 expression postpartum. In sum, we provide evidence that vitamin D anti-tumor activity is mediated through immunomodulatory mechanisms and is ineffective in the post-wean window due to altered hepatic metabolism. These findings have implications for suppressed xenobiotic metabolism in postpartum women beyond vitamin D.

Status of breast cancer detection in young women and potential of liquid biopsy.

Young onset breast cancer (YOBC) is an increasing demographic with unique biology, limited screening, and poor outcomes. Further, women with postpartum breast cancers (PPBCs), cancers occurring up to 10 years after childbirth, have worse outcomes than other young breast cancer patients matched for tumor stage and subtype. Early-stage detection of YOBC is critical for improving outcomes. However, most young women (under 45) do not meet current age guidelines for routine mammographic screening and are thus an underserved population. Other challenges to early detection in this population include reduced performance of standard of care mammography and reduced awareness. Women often face significant barriers in accessing health care during the postpartum period and disadvantaged communities face compounding barriers due to systemic health care inequities. Blood tests and liquid biopsies targeting early detection may provide an attractive option to help address these challenges. Test development in this area includes understanding of the unique biology involved in YOBC and in particular PPBCs that tend to be more aggressive and deadly. In this review, we will present the status of breast cancer screening and detection in young women, provide a summary of some unique biological features of YOBC, and discuss the potential for blood tests and liquid biopsy platforms to address current shortcomings in timely, equitable detection.

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants.

Importance: In young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown. Objective: To determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs. Design, Setting, and Participants: This prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023. Exposure: Time between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years. Main Outcomes and Measures: The primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status. Results: Among 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]). Conclusions and Relevance: These findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage.

In breast cancer, progression to invasive ductal carcinoma (IDC) involves interactions between immune, myoepithelial, and tumor cells. Development of IDC can proceed through ductal carcinoma in situ (DCIS), a non-obligate, non-invasive stage, or IDC can develop without evidence of DCIS and these cases associate with poorer prognosis. Tractable, immune-competent mouse models are needed to help delineate distinct mechanisms of local tumor cell invasion and prognostic implications. To address these gaps, we delivered murine mammary carcinoma cell lines directly into the main mammary lactiferous duct of immune-competent mice. Using two strains of immune-competent mice (BALB/c, C57BL/6), one immune-compromised (severe combined immunodeficiency; SCID) C57BL/6 strain, and six different murine mammary cancer cell lines (D2.OR, D2A1, 4T1, EMT6, EO771, Py230), we found early loss of ductal myoepithelial cell differentiation markers p63, α-smooth muscle actin, and calponin, and rapid formation of IDC in the absence of DCIS. Rapid IDC formation also occurred in the absence of adaptive immunity. Combined, these studies demonstrate that loss of myoepithelial barrier function does not require an intact immune system, and suggest that these isogenic murine models may prove a useful tool to study IDC in the absence of a non-obligatory DCIS stage-an under-investigated subset of poor prognostic human breast cancer.

Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX-2 expression.

BACKGROUND: We investigated the associations of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX-2 protein expression. METHODS: This study included 421 cases and 3,166 controls from a nested case-control study within the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all biannual questionnaires preceding the reference date. Immunochemistry for COX-2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2- breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided. RESULTS: In multivariate analysis, we found no differences in associations of the aspirin exposures and NSAIDs with breast cancer risk by COX2 expression status. In stratified analyses by COX2 status, significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for > 5 tablets per week vs. none 1.71, 95% CI 1.01-2.88, p-trend 0.04). Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend = 0.06). CONCLUSIONS: Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2- tumors.

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah.

Importance: Breast cancer diagnosed within 5 to 10 years after childbirth, called postpartum breast cancer (PPBC), is associated with increased risk for metastasis and death. Whether a postpartum diagnosis is an independent risk factor or a surrogate marker of cancer features associated with poor outcomes remains understudied. Objective: To determine whether diagnostic temporal proximity to childbirth is associated with features of breast cancer associated with poor outcomes, including tumor stage, estrogen receptor (ER) status, and risk for distant metastasis and breast cancer-specific mortality, using a population database from the state of Utah. Design, Setting, and Participants: This population-based cohort study using the Utah Population Database (UPDB) included individuals with stage I to III breast cancer diagnosed at age 45 years or younger between 1996 and 2017, followed-up until February 2020. Participant data were analyzed from November 2019 to August 2022. Exposure: The primary exposures were no prior childbirth or time between most recent childbirth and breast cancer diagnosis. Patients were grouped by diagnoses within less than 5 years, 5 to less than 10 years, or 10 years or more since recent childbirth. Main Outcomes and Measures: The 2 primary outcomes were distant metastasis-free survival and breast cancer-specific death. Cox proportional hazard models were used to investigate associations between exposures and outcomes adjusting for diagnosis year, patient age, tumor stage, and estrogen receptor (ER) status. Results: Of 2970 individuals with breast cancer diagnosed at age 45 years or younger (mean [SD] age, 39.3 [5.0] years; 12 Black individuals [0.4%], 2679 White individuals [90.2%]), breast cancer diagnosis within 5 years of recent childbirth was independently associated with approximately 1.5-fold elevated risk for metastasis (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0) and breast cancer-specific death (HR, 1.5; 95% CI, 1.1-2.1) compared with nulliparous individuals. For cancers classically considered to have tumor features associated with good outcomes (ie, stage I or II and ER-positive), a postpartum diagnosis was a dominant feature associated with increased risk for metastasis and death (eg, for individuals with ER-positive disease diagnosed within <5 years of childbirth: age-adjusted metastasis HR, 1.5; 95% CI, 1.1-2.1; P = .01; age-adjusted death HR, 1.5; 95% CI, 1.0-2.1; P = .04) compared with nulliparous individuals. Furthermore, liver metastases were specifically increased in the group with diagnosis within 5 years postpartum and with positive ER expression (38 of 83 patients [45.8%]) compared with the nulliparous (28 of 77 patients [36.4%]), although the difference was not statistically significant. Overall, these data implicate parity-associated breast and liver biology in the observed poor outcomes of PPBC. Conclusions and Relevance: In this cohort study of individuals with breast cancer diagnosed at age 45 years or younger, a postpartum breast cancer diagnosis was a risk factor associated with poor outcomes. Irrespective of ER status, clinical consideration of time between most recent childbirth and breast cancer diagnosis could increase accuracy of prognosis in patients with young-onset breast cancer.

Body Mass Index Is Inversely Associated with Risk of Postmenopausal Interval Breast Cancer: Results from the Women's Health Initiative.

Interval breast cancer refers to cancer diagnosed after a negative screening mammogram and before the next scheduled screening mammogram. Interval breast cancer has worse prognosis than screening-detected cancer. Body mass index (BMI) influences the accuracy of mammography and overall postmenopausal breast cancer risk, yet how is obesity associated with postmenopausal interval breast cancer incidence is unclear. The current study included cancer-free postmenopausal women aged 50-79 years at enrollment in the Women's Health Initiative who were diagnosed with breast cancer during follow-up. Analyses include 324 interval breast cancer cases diagnosed within one year after the participant's last negative screening mammogram and 1969 screening-detected breast cancer patients. Obesity (BMI ≥ 30 kg/m2) was measured at baseline. Associations between obesity and incidence of interval cancer were determined by sequential logistic regression analyses. In multivariable-adjusted models, obesity was inversely associated with interval breast cancer risk [OR (95% CI) = 0.65 (0.46, 0.92)]. The inverse association persisted after excluding women diagnosed within 2 years [OR (95% CI) = 0.60 (0.42, 0.87)] or 4 years [OR (95% CI) = 0.56 (0.37, 0.86)] of enrollment, suggesting consistency of the association regardless of screening practices prior to trial entry. These findings warrant confirmation in studies with body composition measures.

A multiplex implantable microdevice assay identifies synergistic combinations of cancer immunotherapies and conventional drugs.

Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days. In vivo studies in three immunocompetent mammary carcinoma models demonstrated that the predicted combinations synergistically increased therapeutic efficacy. We identified at least five promising treatment strategies, of which the panobinostat, venetoclax and anti-CD40 triple therapy was the most effective in inducing complete tumor remission across models. Successful drug combinations increased spatial association of cancer stem cells with dendritic cells during immunogenic cell death, suggesting this as an important mechanism of action in long-term breast cancer control.

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

BACKGROUND: Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. METHODS: We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. We tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. RESULTS: In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (i.e., BDNF, TNFα, FGF-2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1 in mammary adipose, and reduced phosphorylated FGFR indicating reduced FGF signaling in tumors. CONCLUSIONS: Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multi-factorial, and that weight maintenance during the peri-/postmenopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

Overall survival is the lowest among young women with postpartum breast cancer.

BACKGROUND: Women diagnosed with breast cancer prior to age 45 years (<45y) and within the first 5 years postpartum (postpartum breast cancer, PPBC) have the greatest risk for distal metastatic recurrence. METHODS: Pooling data from the Colorado Young Women Breast Cancer cohort and the Breast Cancer Health Disparities Study (N = 2519 cases), we examined the association of parity, age, and clinical factors with overall survival (OS) of breast cancer over 15 years of follow-up. RESULTS: Women with PPBC diagnosed at <45y had the lowest OS (p < 0.0001), while OS of nulliparous cases diagnosed at <45y did not differ from OS of cases diagnosed at 45-65y regardless of parity status. After adjustment for study site, race/ethnicity, clinical stage, year of diagnosis and stratification for oestrogen receptor status, PPBC remained an independent factor associated with poor OS. Among cases diagnosed at <45y, nulliparous cases had 1.6 times better OS (hazard ratio (HR) = 0.61, 95%CI 0.42-0.87) compared to those with PPBC, with a more pronounced survival difference among stage I breast cancers (HR = 0.30, 95%CI 0.11-0.79). Among very young women diagnosed at age ≤35y, nulliparous cases had 2.3 times better OS (HR = 0.44, 95%CI 0.23-0.84) compared to PPBC. CONCLUSION: Our results suggest that postpartum status is the main driver of poor prognosis in young women with breast cancer, with the strongest association in patients diagnosed at age ≤35y and in those with stage I disease.

Diet-Driven Inflammation and Insulinemia and Risk of Interval Breast Cancer.

Interval breast cancers (IBCs) emerge after a non-suspicious mammogram and before the patient's next scheduled screen. Risk factors associated with IBC have not been identified. This study evaluated if the empirical dietary inflammatory pattern (EDIP) or empirical dietary index for hyperinsulinemia (EDIH) scores are associated with IBC compared to screen-detected breast cancer. Data were from women 50-79 years-old in the Women's Health Initiative cohort who completed food frequency questionnaires at baseline (1993-98) and were followed through March 31, 2019 for breast cancer detection. Women were identified as having either IBC diagnosed within 1-year after their last negative screening mammogram (N = 317) or screen-detected breast cancer (N = 1,928). Multivariable-adjusted logistic regression analyses were used to estimate odds ratios for risk of IBC compared to screen-detected cancer in dietary index tertiles. No associations were observed between EDIP or EDIH and IBC. Odds ratios comparing the highest to the lowest dietary index tertile were 1.08; 95%CI, 0.78-1.48 for EDIP and 0.92; 95%CI, 0.67-1.27 for EDIH. The null associations persisted when stratified by BMI categories. Findings suggest that diet-driven inflammation or insulinemia may not be substantially associated with IBC risk among postmenopausal women. Future studies are warranted to identify modifiable factors for IBC prevention.

Mammary collagen is under reproductive control with implications for breast cancer.

Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.

Molecular and Clinical Characterization of Postpartum-Associated Breast Cancer in the Carolina Breast Cancer Study Phase I-III, 1993-2013.

BACKGROUND: Breast cancers in recently postpartum women may have worse outcomes, but studies examining tumor molecular features by pregnancy recency have shown conflicting results. METHODS: This analysis used Carolina Breast Cancer Study data to examine clinical and molecular tumor features among women less than 50 years of age who were recently (≤10 years prior) or remotely (>10 years prior) postpartum, or nulliparous. Prevalence odds ratios (POR) and 95% confidence intervals (CI) were estimated using multivariable models. RESULTS: Recently postpartum women (N = 618) were more frequently lymph node-positive [POR (95% CI): 1.66 (1.26-2.19)], estrogen receptor (ER)-negative [1.37 (1.02-1.83)], and IHC-based triple negative [1.57 (1.00-2.47)] compared with nulliparous (N = 360) women. Some differences were identified between recent versus remotely postpartum; smaller tumor size [0.67 (0.52-0.86)], p53 wildtype [0.53 (0.36-0.77)], and non-basal-like phenotype [0.53 (0.33-0.84)] were more common among recently postpartum. Recently postpartum (vs. nulliparous) had significant enrichment for adaptive immunity, T cells, B cells, CD8 T cells, activated CD8 T cells/natural killer (NK) cells, and T follicular helper (Tfh) cells and higher overall immune cell scores. These differences were attenuated in remotely (compared with recently) postpartum women. CONCLUSIONS: These results suggest a dominant effect of parity (vs. nulliparity) and a lesser effect of pregnancy recency on tumor molecular features, although tumor immune microenvironments were altered in association with pregnancy recency. IMPACT: Our study is unique in examining tumor immune microenvironment and RNA-based markers according to time since last childbirth. Future studies should examine the interplay between tumor features, postdiagnostic treatment, and outcomes among recently postpartum women. See related commentary by McDonald et al., p. 518.

Identifying phenotype-associated subpopulations by integrating bulk and single-cell sequencing data.

Single-cell RNA sequencing (scRNA-seq) distinguishes cell types, states and lineages within the context of heterogeneous tissues. However, current single-cell data cannot directly link cell clusters with specific phenotypes. Here we present Scissor, a method that identifies cell subpopulations from single-cell data that are associated with a given phenotype. Scissor integrates phenotype-associated bulk expression data and single-cell data by first quantifying the similarity between each single cell and each bulk sample. It then optimizes a regression model on the correlation matrix with the sample phenotype to identify relevant subpopulations. Applied to a lung cancer scRNA-seq dataset, Scissor identified subsets of cells associated with worse survival and with TP53 mutations. In melanoma, Scissor discerned a T cell subpopulation with low PDCD1/CTLA4 and high TCF7 expression associated with an immunotherapy response. Beyond cancer, Scissor was effective in interpreting facioscapulohumeral muscular dystrophy and Alzheimer's disease datasets. Scissor identifies biologically and clinically relevant cell subpopulations from single-cell assays by leveraging phenotype and bulk-omics datasets.

Pregnancy and weaning regulate human maternal liver size and function.

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.

Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes.

Young women's breast cancer (YWBC) has poor prognosis and known interactions with parity. Women diagnosed within 5-10 years of childbirth, defined as postpartum breast cancer (PPBC), have poorer prognosis compared to age, stage, and biologic subtype-matched nulliparous patients. Genomic differences that explain this poor prognosis remain unknown. In this study, using RNA expression data from clinically matched estrogen receptor positive (ER+) cases (n = 16), we observe that ER+ YWBC can be differentiated based on a postpartum or nulliparous diagnosis. The gene expression signatures of PPBC are consistent with increased cell cycle, T-cell activation and reduced estrogen receptor and TP53 signaling. When applied to a large YWBC cohort, these signatures for ER+ PPBC associate with significantly reduced 15-year survival rates in high compared to low expressing cases. Cumulatively these results provide evidence that PPBC is a unique entity within YWBC with poor prognostic phenotypes.

Vitamin D as a Potential Preventive Agent For Young Women's Breast Cancer.

Clinical studies backed by research in animal models suggest that vitamin D may protect against the development of breast cancer, implicating vitamin D as a promising candidate for breast cancer prevention. However, despite clear preclinical evidence showing protective roles for vitamin D, broadly targeted clinical trials of vitamin D supplementation have yielded conflicting findings, highlighting the complexity of translating preclinical data to efficacy in humans. While vitamin D supplementation targeted to high-risk populations is a strategy anticipated to increase prevention efficacy, a complimentary approach is to target transient, developmental windows of elevated breast cancer risk. Postpartum mammary gland involution represents a developmental window of increased breast cancer promotion that may be poised for vitamin D supplementation. Targeting the window of involution with short-term vitamin D intervention may offer a simple, cost-effective approach for the prevention of breast cancers that develop postpartum. In this review, we highlight epidemiologic and preclinical studies linking vitamin D deficiency with breast cancer development. We discuss the underlying mechanisms through which vitamin D deficiency contributes to cancer development, with an emphasis on the anti-inflammatory activity of vitamin D. We also discuss current evidence for vitamin D as an immunotherapeutic agent and the potential for vitamin D as a preventative strategy for young woman's breast cancer.