Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in vitro drug screens that were consistent with in vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.

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The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67, HER-2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67-expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell-cycle and apoptosis-related proteins, indicating an increased risk of developing tubal cancer.

BACKGROUNDHypoxia‐inducible factor‐1 (HIF‐1) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis to survive cellular hypoxia. Increased levels of HIF‐1α, the O2‐regulated subunit of HIF‐1, were noted during breast carcinogenesis. In this study, the prognostic value of HIF‐1α expression and its correlation with various clinicopathologic variables in patients with invasive breast carcinoma were investigated.METHODSExpression levels of HIF‐1α, HER‐2/neu, estrogen receptor, and progesterone receptor were analyzed in 150 patients with early‐stage breast carcinoma by immunohistochemistry. HER‐2/neu gene amplification was investigated with automated fluorescent in situ hybridization. The mitotic activity index, histologic grade, and tumor type were assessed in hematoxylin and eosinstained specimens. Clinical data included disease‐free survival, overall survival, lymph node status, and tumor size. The data were analyzed with two‐sided univariate and multivariate tests, with P values < 0.05 considered significant.RESULTSHigh levels of HIF‐1α had an association of borderline significance with decreased overall survival (P = 0.059) and disease‐free survival (P = 0.110) that was ascribed completely to the subgroup of women with lymph node negative tumors (n = 81 patients; P = 0.008 and P = 0.004, respectively). HER‐2/neu immunoreactivity (P < 0.001) and gene amplification (P < 0.001), vascular endothelial growth factor expression (P = 0.016), and Ki‐67 expression (P < 0.001) were correlated strongly with HIF‐1α positivity, although none of those factors had an independent effect on survival.CONCLUSIONSIncreased levels of HIF‐1α were associated independently with shortened survival in patients with lymph node negative breast carcinoma. Therefore, the use of immunohistochemical assessment of HIF‐1α as a new predictor of poor outcome may improve clinical decision‐making regarding adjuvant treatment of patients with lymph node negative breast carcinoma. Cancer 2003;97:1573–81. © 2003 American Cancer Society.DOI 10.1002/cncr.11246

(18)FDG uptake in breast cancer is a function of microvasculature for delivering nutrients, Glut-1 for transportation of (18)FDG into the cell, HK for entering (18)FDG into glycolysis, number of tumor cells/volume, proliferation rate (also reflected in necrosis), number of lymphocytes (not macrophages), and HIF-1alpha for upregulating Glut-1. Together, these features explain why breast cancers vary in (18)FDG uptake and elucidate the low uptake in lobular breast cancer.

This paper presents an overview of methods that have been proposed for the analysis of breast cancer histopathology images. This research area has become particularly relevant with the advent of whole slide imaging (WSI) scanners, which can perform cost-effective and high-throughput histopathology slide digitization, and which aim at replacing the optical microscope as the primary tool used by pathologist. Breast cancer is the most prevalent form of cancers among women, and image analysis methods that target this disease have a huge potential to reduce the workload in a typical pathology lab and to improve the quality of the interpretation. This paper is meant as an introduction for nonexperts. It starts with an overview of the tissue preparation, staining and slide digitization processes followed by a discussion of the different image processing techniques and applications, ranging from analysis of tissue staining to computer-aided diagnosis, and prognosis of breast cancer patients.

Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3–β-catenin axis and inhibited non-homologous end joining—the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy.

Introduction Transsexual people receive cross-sex hormones as part of their treatment, potentially inducing hormone-sensitive malignancies. Aim To examine the occurrence of breast cancer in a large cohort of Dutch male and female transsexual persons, also evaluating whether the epidemiology accords with the natal sex or the new sex. Main Outcome Measure Number of people with breast cancer between 1975 and 2011. Methods We researched the occurrence of breast cancer among transsexual persons 18–80 years with an exposure to cross-sex hormones between 5 to &gt;30 years. Our study included 2,307 male-to-female (MtF) transsexual persons undergoing androgen deprivation and estrogen administration (52,370 person-years of exposure), and 795 female-to-male (FtM) subjects receiving testosterone (15,974 total years of exposure). Results Among MtF individuals one case was encountered, as well as a probable but not proven second case. The estimated rate of 4.1 per 100,000 person-years (95% confidence interval [CI]: 0.8–13.0) was lower than expected if these two cases are regarded as female breast cancer, but within expectations if viewed as male breast cancer. In FtM subjects, who were younger and had shorter exposure to cross-sex hormones compared with the MtF group, one breast cancer case occurred. This translated into a rate of 5.9 per 100,000 person-years (95% CI: 0.5–27.4), again lower than expected for female breast cancer but within expected norms for male breast cancer. Conclusions The number of people studied and duration of hormone exposure are limited but it would appear that cross-sex hormone administration does not increase the risk of breast cancer development, in either MtF or FtM transsexual individuals. Breast carcinoma incidences in both groups are comparable to male breast cancers. Cross-sex hormone treatment of transsexual subjects does not seem to be associated with an increased risk of malignant breast development.