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Background: The usefulness of 3D deep learning-based classification of breast cancer and malignancy localization from MRI has been reported. This work can potentially be very useful in the clinical domain and aid radiologists in breast cancer diagnosis., Purpose: To evaluate the efficacy of 3D deep convolutional neural network (CNN) for diagnosing breast cancer and localizing the lesions at dynamic contrast enhanced (DCE) MRI data in a weakly supervised manner., Study Type: Retrospective study., Subjects: A total of 1537 female study cases (mean age 47.5 years ±11.8) were collected from March 2013 to December 2016. All the cases had labels of the pathology results as well as BI-RADS categories assessed by radiologists., Field Strength/sequence: 1.5 T dynamic contrast-enhanced MRI., Assessment: Deep 3D densely connected networks were trained under image-level supervision to automatically classify the images and localize the lesions. The dataset was randomly divided into training (1073), validation (157), and testing (307) subsets., Statistical Tests: Accuracy, sensitivity, specificity, area under receiver operating characteristic curve (ROC), and the McNemar test for breast cancer classification. Dice similarity for breast cancer localization., Results: The final algorithm performance for breast cancer diagnosis showed 83.7% (257 out of 307) accuracy (95% confidence interval [CI]: 79.1%, 87.4%), 90.8% (187 out of 206) sensitivity (95% CI: 80.6%, 94.1%), 69.3% (70 out of 101) specificity (95% CI: 59.7%, 77.5%), with the area under the curve ROC of 0.859. The weakly supervised cancer detection showed an overall Dice distance of 0.501 ± 0.274., Data Conclusion: 3D CNNs demonstrated high accuracy for diagnosing breast cancer. The weakly supervised learning method showed promise for localizing lesions in volumetric radiology images with only image-level labels., Level of Evidence: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1144-1151., (© 2019 International Society for Magnetic Resonance in Medicine.)

Introduction: Tobacco smoke is known to be the main cause of lung, head and neck tumors. Recently, evidence for an increasing breast cancer risk associated with tobacco smoke exposure has been emerging. We and other groups have shown that nicotine, as a non-conventional carcinogen, has the potential to facilitate cancer genesis and progression. However, the underlying mechanisms by which the smoke affects the breast, rather than the lung, remain unclear. Here, we examine possible downstream signaling pathways of the nicotinic acetylcholine receptor (nAChR) and their role in breast cancer promotion., Methods: Using human benign MCF10A and malignant MDA-MB-231 breast cells and specific inhibitors of possible downstream kinases, we identified nAChR effectors that were activated by treatment with nicotine. We further tested the effects of these effector pathways on the regulation of E2F1 activation, cell cycle progression and on Bcl-2 expression and long-term cell survival., Results: In this study, we demonstrated a novel signaling mechanism by which nicotine exposure activated Src to sensitize epidermal growth factor receptor (EGFR)-mediated pathways for breast cancer cell growth promotion. After the ligation of nAChR with nicotine, EGFR was shown to be activated and then internalized in both MCF10A and MDA-MB-231 breast cancer cells. Subsequently, Src, Akt and ERK1/2 were phosphorylated at different time points following nicotine treatment. We further demonstrated that through Src, the ligation of nicotine with nAChR stimulated the EGFR/ERK1/2 pathway for the activation of E2F1 and further cell progression. Our data also showed that Akt functioned directly downstream of Src and was responsible for the increase of Bcl-2 expression and long-term cell survival., Conclusions: Our study reveals the existence of a potential, regulatory network governed by the interaction of nicotine and nAChR that integrates the conventional, mitogenic Src and EGFR signals for breast cancer development.

Nicotine, one of the major components in tobacco, is at high concentrations in the bloodstream of cigarette smokers. However, the mechanisms of how nicotine affects tumor development and whether nicotine is a potential carcinogen for malignancies induced by secondhand smoking are not fully understood yet. Here, we investigate the signaling pathways by which nicotine potentiates tumorigenesis in human mammary epithelial-like MCF10A or cancerous MCF7 cells. We show that human MCF10A and MCF7 cells both express four subunits of nicotine acetylcholine receptor (nAChR). The treatment of these cells with nicotine enhances the activity of protein kinase C (PKC) alpha without altering the expression level of this kinase. Nicotine also stimulates [(3)H]thymidine incorporation into the genome of these cells as well as forces serum-starved cells to enter S phase of the cell cycle, resulting in growth promotion. Importantly, on nicotine treatment, the mobility of MCF10A and MCF7 cells is enhanced, which can be blocked by the addition of nAChR or PKC inhibitor. Experiments using small interfering RNA knockdown or ectopic expression of cdc42 showed that cdc42 functions as a downstream effector of PKC and is crucial in the regulation of nicotine-mediated migratory activity in the cells. Together, our findings suggest that nicotine, through interacting with its receptor, initiates a signaling cascade that involves PKC and cdc42 and consequently promotes migration in mammary epithelial or tumor cells.

The human tissue kallikreins are secreted serine proteases, encoded by a group of homologous genes clustered in tandem on chromosome 19q13.3-4. Human kallikrein 6 and human kallikrein 10 are two new members of this family. Recently, we developed highly sensitive and specific immunofluorometric assays for human kallikrein 6 and human kallikrein 10, which allow for their quantification in tissue extracts and biological fluids. Both human kallikrein 6 and human kallikrein 10 are found to be down-regulated in breast cancer cell lines, suggesting that they may be involved in breast cancer pathogenesis and progression. In this study, we investigated the potential value of human kallikrein 6 and human kallikrein 10 as prognostic and predictive factors in breast cancer. We quantified human kallikrein 6 and human kallikrein 10 protein levels in 749 breast tumour cytosolic extracts and correlated this data with various clinicopathological variables and patient outcomes. Human kallikrein 6 and human kallikrein 10 are positively correlated with each other. Higher human kallikrein 6 and human kallikrein 10 protein levels are associated with younger age, pre-menopausal, status and tumours which are negative for oestrogen and progesterone receptors. No correlation was found between human kallikrein 6 and human kallikrein 10 levels and tumour size, grade, and nodal status. Survival analysis showed that neither human kallikrein 6 nor human kallikrein 10 are related to the rate of relapse-free and overall survival. In the analysis with respect to response to tamoxifen therapy, although human kallikrein 6 levels were not associated with tamoxifen responsiveness, higher levels of human kallikrein 10 were significantly associated with a poor response rate. This association remained significant in the multivariate analysis. Furthermore, higher human kallikrein 10 levels were significantly related with a short progression-free and post-relapse overall survival after start of tamoxifen treatment for advanced disease. Taken together, our results suggest that although human kallikrein 6 and human kallikrein 10 are not prognostic markers for breast cancer, human kallikrein 10 is an independent predictive marker for response of tamoxifen therapy., (Copyright 2002 Cancer Research UK)

Background: The KLK10 gene (also known as the normal epithelial cell-specific 1 gene) is a member of the expanded human kallikrein gene family. Recently, it has been reported that KLK10 is a tumor suppressor gene and that its expression is downregulated in various forms of cancer and cancer cell lines. KLK10 is also upregulated in ovarian cancer. We thus hypothesized that the KLK10 gene may be a target for mutations in various cancers., Methods: We sequenced the five coding exons of the KLK10 gene using genomic DNA from various tumors, normal tissues, and blood, by PCR amplification and automated sequencing., Results: In none of the tumor-derived DNAs, we identified somatic mutations that could inactivate this gene. However, we identified a prevalent germline single nucleotide variation at codon 50 (exon 3) of this gene [GCC (alanine) to TCC (serine)]. The GCC genotype was less prevalent in prostatic cancer patients in comparison to control subjects (P = 0.027) but no differences were seen with testicular, ovarian, and breast cancer. We also identified four genetic variations in exon 4, at codons106 [GGC (glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC (threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and at codon 149 [CCG (proline) to CTG (leucine)]. None of these variations was significantly different between normal subjects and cancer groups., Conclusions: We found no evidence for somatic mutations of the KLK10 gene in cancers of the prostate, breast, ovary, and testis. The single nucleotide variation at codon 50 appears to be associated with prostate cancer risk., (Copyright 2002 Wiley-Liss, Inc.)

The normal epithelial cell-specific 1 (NES1) gene encodes a serine protease which was found to be down-regulated in breast cancer. There is evidence that NES1 acts as a tumor suppressor gene in breast cancer cells. To further understand its role in breast tumorigenesis, we investigated the effect of estrogens, androgens, and progestins on NES1 gene expression, in the breast cancer cell line BT-474, at the transcription level. The reverse transcriptase polymerase chain reaction method was used to monitor changes in the NES1 mRNA. Our experiments showed that NES1 gene expression is up-regulated promptly in response to 17 beta-estradiol, 5 alpha-dihydrotestosterone (DHT) and norgestrel stimulation. NES1 gene mRNA started to increase 2 hours after estradiol stimulation and 8 hours after DHT stimulation. The stimulation of NES1 by estradiol can be dramatically blocked by the estrogen antagonists ICI 182,780 and 4-hydroxytamoxifen. Mifepristone (a synthetic antiprogestin) can partially block the up-regulation of the NES1 gene by norgestrel. Dose-response experiments indicated that the lowest stimulatory concentration of 17 beta-estradiol, DHT, and norgestrel is 10(-11) M, 10(-10) M, and 10(-10) M, respectively. The production of NES1 mRNA increased coordinately with increasing concentration of the stimulants. These results suggest that the NES1 gene is primarily regulated by estrogen, but also by androgen and progestin in the breast cancer cell line BT-474. It appears that NES1 may be involved in a pathway that counter balances the action of estrogens and androgens in steroid hormone responsive tissues.