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Through the concerted efforts of many patients, health-care providers, legislators, and other supporters, the past decade has seen the development of the first clinics dedicated to the care of patients with inflammatory breast cancer in the USA and other countries. Together with social networking, advocacy, and education, a few specialised centres have had substantial increases in patient numbers (in some cases ten times higher), which has further expanded the community of science and advocacy and increased the understanding of the disease process. Although inflammatory breast cancer is considered rare, constituting only 2–4% of breast cancer cases, poor prognosis means that patients with the disease account for roughly 10% of breast cancer mortality annually in the USA. I propose that the unique presentation of inflammatory breast cancer might require specific, identifiable changes in the breast parenchyma that occur before the tumour-initiating event. This would make the breast tissue itself a tumour-promoting medium that should be treated as a component of the pathology in multidisciplinary treatment and should be further studied for complementary targets to inhibit the pathobiology that is specific to inflammatory breast cancer.

Epithelial–mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo . Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance. Ma and colleagues show that when the EMT-associated transcription factor ZEB1 is stabilized by the ATM kinase, it interacts with the ubiquitin protease USP7 to counteract CHK1 degradation and promote DNA repair in breast cancer cells.

Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination. We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

Background Trastuzumab, combined with chemotherapy, is the current standard treatment for both metastatic and early-stage HER2-positive (HER2 +) breast cancer. One of the mechanisms of action of trastuzumab is antibody-dependent cellular cytotoxicity (ADCC), which involves engaging FcγRIIIA (CD16) on natural killer (NK) cells. A competent immune system and properly functioning NK cells are crucial for effective ADCC, as they can influence favorable clinical outcomes. Resistance to trastuzumab often develops after about one year. We previously reported that elevated levels of miR-19a-3p in the serum of patients with metastatic HER2 + breast cancer treated with trastuzumab were associated with a favorable prognosis. Here, we aim to identify the mechanism and the immune cells responsible for elevated serum levels of miR-19a-3p. Methods Peripheral blood mononuclear cells (PBMCs) from healthy individuals were used to isolate naïve CD4 + T cells and NK cells. Naïve CD4 + T cells were polarized into CD4 + Th1 and CD4 + Th2 cells. NK cells were utilized for the ADCC assay. Levels of transcription factors, cytokines, and miR-19a-3p were measured using RT-qPCR. Surface markers and cytokines were analyzed by flow cytometry to characterize immune cell phenotypes. Results In vitro NK cell-mediated ADCC resulted in increased levels of miR-19a-3p released into the supernatants after killing breast cancer cells. In vitro polarized CD4 + Th1 cells expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. Over a long-term in vitro culture (24 days), anti-CD3/CD28 restimulation sustained higher levels of miR-19a-3p in CD4 + Th1 cells compared to CD4 + Th2 cells and their respective supernatants. CD4 + Th1 cells developed a central memory T (T CM ) phenotype (CD45RO + CCR7 + CD62L +) and expressed and secreted higher levels of miR-19a-3p than CD4 + Th2 cells. In patients with HER2 + metastatic breast cancer, those with elevated serum levels of miR-19a-3p and a favorable prognosis had a larger percentage of circulating activated T cells and NK cells in their blood compared to patients with lower serum levels of miR-19a-3p and a poor prognosis. The small cohort (n = 15) limits the statistical power of our retrospective study. Discussion Our findings suggest that elevated levels of miR-19a-3p in the serum of patients with HER2 + metastatic breast cancer may result from effective NK cell-mediated ADCC and activation of CD4 + Th1 cells, which could be responsible for the anti-tumor immune response associated with a favorable prognosis. Blood levels of miR-19a-3p might help identify breast cancer patients who have effective trastuzumab-induced anti-tumor immune responses.

Recent studies have identified a subpopulation of highly tumorigenic cells with stem/progenitor cell properties from human breast cancers, and it has been suggested that stem/progenitor cells, which remain after breast cancer therapy, may give rise to recurrent disease. We hypothesized that progenitor cells are resistant to radiation, a component of conventional breast cancer therapy, and that that resistance is mediated at least in part by Wnt signaling, which has been implicated in stem cell survival. To test this hypothesis, we investigated radioresistance by treating primary BALB/c mouse mammary epithelial cells with clinically relevant doses of radiation and found enrichment in normal progenitor cells (stem cell antigen 1-positive and side population progenitors). Radiation selectively enriched for progenitors in mammary epithelial cells isolated from transgenic mice with activated Wnt/β-catenin signaling but not for background-matched controls, and irradiated stem cell antigen 1-positive cells had a selective increase in active β-catenin and survivin expression compared with stem cell antigen 1-negative cells. In clonogenic assays, colony formation in the stem cell antigen 1-positive progenitors was unaffected by clinically relevant doses of radiation. Radiation also induced enrichment of side population progenitors in the human breast cancer cell line MCF-7. These data demonstrate that, compared with differentiated cells, progenitor cells have different cell survival properties that may facilitate the development of targeted antiprogenitor cell therapies.

Background Breast cancer patients who undergo regional nodal irradiation therapy (RNI) following neoadjuvant chemotherapy and mastectomy or lumpectomy with axillary lymph node dissection (ALND) frequently encounter breast cancer-related lymphedema (BCRL). Early detection and treatment can significantly improve outcomes. Previously, near-infrared fluorescence lymphatic imaging (NIRF-LI) detection of dermal backflow, or retrograde lymphatic flow into initial lymphatics, was shown to precede clinical BCRL diagnosis by 8–23 months. Herein, we hypothesize that lymphatic pump failure is responsible for dermal backflow and may be a target to prevent onset of BCRL symptoms. Methods Arm lymphatics in 51 patients with locally advanced breast cancer were visualized with NIRF-LI in a prospective, longitudinal, observational clinical cohort study. Lymphatic pumping frequencies were measured to investigate pumping changes during and after breast cancer treatment. Lymphatic pumping was quantified at five timepoints: after neoadjuvant chemotherapy, but before breast cancer excision and ALND, again at four weeks post-ALND, and at 6, 12, and 18 months post-RNI. Repeated measures mixed-effects analysis was used to compare the mean pumping frequencies amongst all time points. Additionally, pairwise comparisons between any two time points were performed using Wilcoxon matched-pairs signed rank test. Results As time lapsed after surgical treatment and RNI, ipsilateral dorsal forearm, ipsilateral ventral forearm, and ventral axilla pumping failure preceded the appearance of dermal backflow and clinically diagnosed BCRL, suggesting that lymphatic pumping dysfunction is the first step in BCRL development. Conclusions This study suggests that impairment of the intrinsic lymph pump may be responsible for the onset of clinical BCRL symptoms, and therefore represents a target for prevention of cancer-acquired lymphedema. Future research is needed to understand the molecular determinants of the intrinsic lymphatic pump, and how cancer treatments and interventions can impact them.

Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

In the absence of histological criteria that distinguish between inflammatory and non-inflammatory breast cancer, diagnosis of inflammatory breast cancer relies entirely on the existence of clinical criteria as outlined by the TNM classification. This classification restricts patients presenting with clinical criteria characteristic of inflammatory breast cancer to subcategory T4d, which immediately relegates all patients with non-metastatic inflammatory breast cancer to stage 3, regardless of tumour size or nodal spread. Patients who present with metastatic disease are consigned to stage 4, and the TNM classification does not distinguish patients on the basis of the presence of inflammatory criteria. Evidence by our group and others suggests that patients with inflammatory breast cancer have significantly reduced overall survival among those who present with distant metastasis at diagnosis (stage 4). In light of these results, this Personal View addresses whether the current TNM staging classification accurately represents a distinction between patients with inflammatory and those with non-inflammatory breast cancer.

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBC's unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy. [PUBLICATION ABSTRACT]

Background Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2−) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Methods Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. Results We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Conclusions Patients with metastatic HR+HER2− IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials.