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A majority of breast cancers (BC) are age-related and we seek to determine what cellular and molecular changes occur in breast tissue with age that make women more susceptible to cancer initiation. Immune-epithelial cell interactions are important during mammary gland development and the immune system plays an important role in BC progression. The composition of human immune cell populations is known to change in peripheral blood with age and in breast tissue during BC progression. Less is known about changes in immune populations in normal breast tissue and how their interactions with mammary epithelia change with age. We quantified densities of T cells, B cells, and macrophage subsets in pathologically normal breast tissue from 122 different women who ranged in age from 24 to 74 years old. Donor-matched peripheral blood from a subset of 20 donors was analyzed by flow cytometry. Tissue immune cell densities and localizations relative to the epithelium were quantified in situ with machine learning-based image analyses of multiplex immunohistochemistry-stained tissue sections. In situ results were corroborated with flow cytometry analyses of peri-epithelial immune cells from primary breast tissue preparations and transcriptome analyses of public data from bulk tissue reduction mammoplasties. Proportions of immune cell subsets in breast tissue and donor-matched peripheral blood were not correlated. Density (cells/mm2) of T and B lymphocytes in situ decreased with age. T cells and macrophages preferentially localized near or within epithelial bilayers, rather than the intralobular stroma. M2 macrophage density was higher than M1 macrophage density and this difference was due to higher density of M2 in the intralobular stroma. Transcriptional signature analyses suggested age-dependent decline in adaptive immune cell populations and functions and increased innate immune cell activity. T cells and macrophages are so intimately associated with the epithelia that they are embedded within the bilayer, suggesting an important role for immune-epithelial cell interactions. Age-associated decreased T cell density in peri-epithelial regions, and increased M2 macrophage density in intralobular stroma suggests the emergence of a tissue microenvironment that is simultaneously immune-senescent and immunosuppressive with age. Supplementary Information The online version contains supplementary material available at 10.1007/s10911-021-09495-2.

Estrogens have pleiotropic effects on many reproductive and non-reproductive tissues and organs including the mammary gland, uterus, ovaries, vagina, and endothelium. Estrogen receptor α functions as the principal mediator of estrogenic action in most of these tissues. Estetrol (E4) is a native fetal estrogen with selective tissue actions that is currently approved for use as the estrogen component in a combined oral contraceptive and is being developed as a menopause hormone therapy (MHT, also known as hormone replacement therapy). However, exogenous hormonal treatments, in particular MHTs, have been shown to promote the growth of preexisting breast cancers and are associated with a variable risk of breast cancer depending on the treatment modality. Therefore, evaluating the safety of E4-based formulations on the breast forms a crucial part of the clinical development process. This review highlights preclinical and clinical studies that have assessed the effects of E4 and E4-progestogen combinations on the mammary gland and breast cancer, focusing in particular on the estrogenic and anti-estrogenic properties of E4. We discuss the potential advantages of E4 over current available estrogen-formulations as a contraceptive and for the treatment of symptoms due to menopause. We also consider the potential of E4 for the treatment of endocrine-resistant breast cancer.

Regions of high mammographic density (MD) in the breast are characterised by a proteoglycan (PG)-rich fibrous stroma, where PGs mediate aligned collagen fibrils to control tissue stiffness and hence the response to mechanical forces. Literature is accumulating to support the notion that mechanical stiffness may drive PG synthesis in the breast contributing to MD. We review emerging patterns in MD and other biological settings, of a positive feedback cycle of force promoting PG synthesis, such as in articular cartilage, due to increased pressure on weight bearing joints. Furthermore, we present evidence to suggest a pro-tumorigenic effect of increased mechanical force on epithelial cells in contexts where PG-mediated, aligned collagen fibrous tissue abounds, with implications for breast cancer development attributable to high MD. Finally, we summarise means through which this positive feedback mechanism of PG synthesis may be intercepted to reduce mechanical force within tissues and thus reduce disease burden.

Lipofilling may constitute a technique to assist reconstruction of breasts following prophylactic mastectomy for patients with mutated BRCA1 or BRCA2 genes. However, to date it is not clear whether adipose-derived stromal cells (ADSCs) increase the risk of tumor initiation and progression in this situation. Therefore, the interactions of BRCA1 mutated breast cancer cell lines with normal ADSCs were investigated in the present study. Characteristics of MDA-MB-436 (BRCA1 c.5277 + 1G > A) and HCC1937 (BRCA1 p.Gln1756.Profs*74) were compared to MDA-MB-231 and T47D BRCA1/2 wild-type breast cancer cell lines. ADSCs were cultivated from lipoaspirates of a panel of BRCA1/2- wildtype patients. Interactions of conditioned medium (CM) of these cells with the breast cancer lines were studied using proliferation and migration assays as well as adipokine expression western blot arrays. CM of ADSCs exhibit a dose-dependent stimulation of the proliferation of the breast cancer cell lines. However, of the ADSC preparations tested, only 1 out of 18 samples showed a significant higher stimulation of BRCA1-mutated MDA-MB-436 versus wildtype MDA-MB-231 cells, and all CM revealed lower stimulatory activity for BRCA1-mutated HCC1937 versus wildtype T47D cells. Additionally, migration of breast cancer cells in response to CM of ADSCs proved to be equivalent or slower for BRCA1/2 mutated versus nonmutated cancer cells and, with exception of angiopoietin-like 2, induced expression of adipokines showed no major difference. Effects of media conditioned by normal ADSCs showed largely comparable effects on BRCA1-mutated and wildtype breast cancer cell lines thus advocating lipofilling, preferentially employing allogeneic non-mutated ADSCs.

Purpose Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval. Methods Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI. Results The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms. Conclusions Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.

Salivary duct carcinomas (SDC) and Her2/Neu3-overexpressing invasive breast carcinomas (HNPIBC/IBC) are histologically indistinguishable. We investigated whether common histopathologic and immunophenotypic features of SDC and IBC are mirrored by a similar microRNA (miRNA) profile. MiRNA profiling of 5 SDCs, 6 IBCs Her2/Neu3+, and 5 high-grade ductal breast carcinoma in situ (DCIS) was performed by NanoString platform. Selected miRNAs and HOXA1 gene were validated by RT-PCR. We observed similar miRNA expression profiles between IBC and SDC with the exception of 2 miRNAs, miR-10a and miR-142-3p, which were higher in IBC tumors. DCIS tumors displayed increased expression of miR-10a, miR-99a, miR-331-3p and miR-335, and decreased expression of miR-15a, miR-16 and miR-19b compared to SDC. The normal salivary gland and breast tissues also showed similar expression profiles. Interestingly, miR-10a was selectively increased in both IBC and normal breast tissue compared to SDC and normal salivary gland tissue. Moreover, our NanoString and RT-PCR data confirmed that miR-10a was upregulated in IBC and DCIS compared to SDC. Finally, we show downregulation of HOXA1, a miR-10 target, in IBC tumors compared to normal breast tissue. Taken together, our data demonstrates that, based on miRNA profiling, SDC is closely related to HNPIBC. Our results also suggest that miR-10a is differentially expressed in IBC compared to SDC and may have potential utility as a diagnostic biomarker in synchronous or metachronous malignant epithelial malignancies involving both organs. In addition, miR-10a could be playing an important role as a mammary-specific oncogene, involved in breast cancer initiation (DCIS) and progression (IBC), through mechanisms that include modulation of HOXA1 gene expression. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-018-0971-x) contains supplementary material, which is available to authorized users.

Breast cancer screening combined with follow-up and treatment reduces breast cancer mortality. However, in the study clinic, only 12 % of eligible women ≥40 years received a mammogram in the previous year. The objective of this project was to implement patient navigation, in our partner health clinic to (1) identify women overdue for a mammogram; and (2) increase mammography utilization in this population over a 2-year period. Women overdue for a mammogram were identified. One patient navigator made navigation attempts over a 2-year period (2009–2011). Navigation included working around systems- and individual-level barriers to receive a mammogram as well as the appropriate follow-up post screening. Women were contacted up to three times to initiate navigation. The proportion of women navigated and who received a mammogram during the study period were compared to women who did not receive a mammogram using Chi square tests for categorical variables and t tests for continuous variables with an α = 0.05. Barriers to previous mammography were also assessed. With 94.8 % of eligible women navigated and 94 % of these women completing mammography, the implementation project reached 89 % of the target population. This project was a successful implementation of an evidence-based patient navigation program that continues to provide significant impact in a high-need area. Cost was the most commonly cite barrier to mammography. Increasing awareness of resources in the community for mammography and follow-up care remains a necessary adjunct to removing structural and financial barriers to accessing preventive services.

Distant metastases are relatively common in breast cancer, but spread to the head and neck region is uncommon and can be diagnostically challenging. Pathology databases of two academic hospitals were searched for patients. The diagnoses were by morphologic comparison with the primary breast specimen (when available) or through the use of immunohistochemical stains characteristic of breast carcinoma (cytokeratin 7, mammaglobin, GCDFP15, and/or GATA3 positive—excluding new primary tumors at the respective head and neck sites). Of the 25 patients identified, only 22 (88.0 %) had a known history of breast carcinoma. Time from primary diagnosis to head and neck metastasis was highly variable, ranging from 1 to 33 years (mean = 10.9 years). The most common locations were neck lymph nodes (8 cases), orbital soft tissue (5), oral cavity (3), skull base (3), mastoid sinus (2), nasal cavity (1), palatine tonsil (1), and facial skin (1). Clinical presentations were highly variable, ranging from cranial nerve palsies without a mass lesion to oral cavity erythema and swelling to bone pain. Histologically, two cases showed mucosal (or skin)-based mass lesions with associated pagetoid spread in the adjacent epithelium, a feature normally associated with primary carcinomas. Three tumors were misdiagnosed pathologically as new head and neck primary tumors. This series demonstrates the extreme variability in clinical and pathologic features of breast cancer metastatic to the head and neck, including long time intervals to metastasis.

Anterior gradient 2 (AGR2) is a promising anti-tumor target associated with estrogen receptor expression and metastatic progression of breast cancer. Insulin-like growth factor-1 (IGF-1) is another potent factor that stimulates breast cancer progression and mediates anti-estrogen drug resistance. However, the precise mechanism and connections between these two factors in breast cancer drug resistance have not been fully elucidated. Here, for the first time, we decipher that IGF-1 remarkably induces AGR2 in the MCF7 cell line, through an estrogen response element (ERE) between −802 and −808 bp and a leucine zipper transcription factor-binding site located between −972 and −982 bp on the AGR2 promoter. We also found that the ERK1/2 and AKT pathways mediate estrogen receptor-α at the upstream of ERE and that the JNK pathway activates the leucine zipper site through the c-Jun/c-Fos complex. Additionally, our data suggest that knockdown of AGR2 reduces IGF-1-induced cell proliferation, migration and cell cycle progression. Therefore, we report that AGR2 is a key modulator involved in IGF-1-induced breast cancer development. We propose that the identification of the mechanism linking the IGF-1/insulin signal and AGR2 promoter activation is important, because it provides insights into the development of anti-breast cancer drugs.

e11553 Background: The aim of the study was to assess the rate, pattern and time of recurrence in patients with triple-negative breast cancer (TNBC) treated in one institution. The second goal was to evaluate factors influencing recurrence and overall survival in this group of patients. Methods: 2534 consecutive breast cancer patients were diagnosed at the Cancer Center and Institute of Oncology in Warsaw, Poland, between January 2005 and December 2006. Out of 2534 patients, 228 (9%) were TNBC (ER/PR/HER2-negative). The clinicopathological characteristics were determined using descriptive statistics. The overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The univariate and multivariate analyses were developed to identify factors influencing recurrence and survival in TNBC patients. Results: Most of the patients were diagnosed with stage II or III breast cancer (47% and 34%, respectively), the median age at diagnosis was 54.5 years. The most common histological type was ductal cancer (81%). 31% of patients were treated with neoadjuvant chemotherapy and 49% with adjuvant chemotherapy – almost all consisted of anthracyclines. 6 years of observation revealed that the metastatic disease occurred in 35% of all TNBC patients: 15% in the brain, 14% in the lungs, 11% in the bones, 8% in the liver and 14% had locoregional relapse. The highest risk of recurrence was during the first 3 years after primary treatment and then during the next two years of observation it did not change. Median DFS and OS were not reached at the time of analysis, 6-year DFS and OS were 68% and 62%, respectively.Factors influencing recurrence were: tumor size and systemic adjuvant chemotherapy while factors influencing overall survival were: tumor size, nodal status, adjuvant/neoadjuvant treatment and metastases in the brain, liver and bones. Conclusions: Characteristic pattern of recurrence in time was revealed. The tumor size was responsible for recurrence despite lack of involvement of lymph nodes. Aggressive adjuvant/neoadjuvant treatment ordered in all clinical stages of TNBC (including N0) was factor responsible for avoiding local and distant relapse and prolonging overall survival.

The aim of the study was to define biological subtypes of breast cancer that have the propensity to metastasize to the leptomeninges and to assess factors influencing survival from detection of leptomeningeal metastatis (LM). One hundred and eighteen consecutive breast cancer patients with LM were treated in one institution, between the years 1999 and 2009; 40.5 % of patients had triple-negative subtype, 37.5 % had luminal A subtype and 22 % had HER2-positive subtypes (luminal B and HER2). Of patients with LM, 35 % had lobular cancer. Median survival from the detection of LM was 18 weeks, and 1-year survival was 16 %. Cox multivariate analysis revealed that performance status and systemic treatment statistically significantly influenced survival of patients with LM. Triple-negative biological subtype and lobular histological type of breast cancer had the propensity to metastasize to the leptomeninges. Performance status and systemic treatment ordered after detection of LM statistically significantly influenced survival.