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The etiology of triple-negative breast cancers (TNBC) is poorly understood. As many TNBCs develop prior to the initiation of breast cancer screening or at younger ages when the sensitivity of mammography is comparatively low, understanding the etiology of TNBCs is critical for discovering novel prevention approaches for these tumors. Furthermore, the higher incidence rate of estrogen receptor-negative breast cancers, and specifically, of TNBCs, among young African American women (AAW) versus white women is a source of racial disparities in breast cancer mortality. Whereas immune responses to TNBCs have received considerable attention in relation to prognosis and treatment, the concept that dysregulated immune responses may predispose to the development of TNBCs has received limited attention. We present evidence that dysregulated immune responses are critical in the pathogenesis of TNBCs, based on the molecular biology of the cancers and the mechanisms proposed to mediate TNBC risk factors. Furthermore, proposed risk factors for TNBC, especially childbearing without breastfeeding, high parity, and obesity, are more prevalent among AAW than white women. Limited data suggest genetic differences in immune responses by race, which favor a stronger Thr type 2 (Th2) immune response among AAW than white women. Th2 responses contribute to wound-healing processes, which are implicated in the pathogenesis of TNBCs. Accordingly, we review data on the link between immune responses and TNBC risk and consider whether the prevalence of risk factors that result in dysregulated immunity is higher among AAW than white women., (©2020 American Association for Cancer Research.)

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8 + T-cell infiltration and activation in vivo , and that CD8 + T-cell depletion severely compromises antitumor efficacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared with HR-proficient TNBC cells and in vivo models. CRISPR-mediated knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T-cell infiltration in vivo . These findings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8 + T-cell recruitment and antitumor efficacy. The data provide insight into the mechanism of action of PARP inhibitors in BRCA -associated breast cancer. This article is highlighted in the In This Issue feature, p. 681 ., (©2019 American Association for Cancer Research.)

Obesity is associated with white adipose tissue (WAT) inflammation in the breast, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that predispose to breast cancer development. We examined whether WAT inflammation and its associated systemic effects correlate with body fat levels in an Asian population where body mass index (BMI) is not an accurate assessment of obesity and cancer risk. We also investigated whether biologic differences could account for the greater proportion of premenopausal estrogen receptor (ER)-positive breast cancer in Asian versus Western countries. Breast WAT and fasting blood were prospectively collected from Taiwanese women undergoing mastectomy for breast cancer treatment. Body composition was measured in a subgroup using bioelectrical impedance analysis. WAT inflammation was defined by the presence of crown-like structures of the breast, which are composed of dead or dying adipocytes surrounded by macrophages. Findings were compared with U.S. Caucasian women. In the Taiwanese cohort ( n = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI ( P < 0.01) and increased levels of body fat ( P < 0.01), C-reactive protein ( P = 0.02), triglycerides ( P < 0.01), insulin resistance scores ( P = 0.04), and lower HDL cholesterol ( P < 0.01). ER + tumors were associated with greater body fat versus other subtypes ( P = 0.03). Compared with U.S. Caucasians ( n = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status ( P = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. Cancer Prev Res; 11(4); 227-36. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Reproductive factors are among the most well-established risk factors for breast cancer. However, their associations with different breast cancer subtypes defined by joint estrogen receptor (ER)/progesterone receptor (PR)/HER2 status remain unclear., Methods: We assessed relationships between reproductive factors and risks of luminal A (ER(+)/HER2(-)), luminal B (ER(+)/HER2(+)), triple-negative (TN; ER(-)/PR(-)/HER2(-)), and HER2-overexpressing (H2E; ER(-)/HER2(+)) breast cancers in a population-based case-case study consisting of 2,710 women ages 20-69 years diagnosed between 2004 and 2012. ORs and 95% confidence intervals (CI) were estimated with luminal A cases serving as the reference group using polytomous logistic regression., Results: Earlier age at first full-term pregnancy and age at menopause were positively associated with odds of TN breast cancer (Ptrend: 0.003 and 0.024, respectively). Parity was associated with a 43% (95% CI, 1.08-1.89) elevated odds of H2E breast cancer, and women who had ≥3 full-term pregnancies had a 63% (95% CI, 1.16-2.29, Ptrend = 0.013) increased odds of this subtype compared with nulliparous women. Breast feeding for ≥36 months was associated with a 49% (OR 0.51; 95% CI, 0.27-0.99) lower odds of TN breast cancer., Conclusion: Our results suggest that reproductive factors contribute differently to risks of the major molecular subtypes of breast cancer., Impact: African American and Hispanic women have higher incidence rates of the more aggressive TN and H2E breast cancers and their younger average age at first pregnancy, higher parity, and less frequent breast feeding could in part contribute to this disparity. Cancer Epidemiol Biomarkers Prev; 25(9); 1297-304. ©2016 AACR., (©2016 American Association for Cancer Research.)