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The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1-JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2-p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy.
Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
Copyright © 2015 Elsevier Inc. All rights reserved.
BACKGROUND - Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions.
METHODS - Our studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium.
RESULTS - We found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue.
CONCLUSIONS - These results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.
PURPOSE - The reproductive windows between age at menarche and age at first birth (standardized age at first birth) and from menarche to menopause (reproductive lifespan) may interact with genetic variants in association with breast cancer risk.
METHODS - We assessed this hypothesis in 6131 breast cancer cases and 7274 controls who participated in the population-based Collaborative Breast Cancer Study. Risk factor information was collected through telephone interviews, and DNA samples were collected on a subsample (N= 1484 cases, 1307 controls) to genotype for 13 genome-wide association study-identified loci. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and P values for the interaction between reproductive windows and genotypes were obtained by adding cross-product terms to statistical models.
RESULTS - For standardized age at first birth, the OR was 1.52 (CI, 1.36-1.71) comparing the highest quintile with the lowest quintile. Carrier status for rs10941679 (5p12) and rs10483813 (RAD51B) appeared to modify this relationship (P = .04 and P = .02, respectively). For reproductive lifespan, the OR comparing the highest quintile with the lowest quintiles was 1.62 (CI, 1.35-1.95). No interactions were detected between genotype and reproductive lifespan (all P > .05). All results were similar regardless of ductal versus lobular breast cancer subtype.
CONCLUSIONS - Our results suggest that the reproductive windows are associated with breast cancer risk and that associations may vary by genetic variants.
Copyright © 2014 Elsevier Inc. All rights reserved.
We recently reported the prevalence of atypical proliferative lesions (APL) in reduction mammoplasty specimens from patients that were treated mainly for macromastia with no known history of breast cancer. The current study is to investigate the prevalence of APLs in breast reduction specimens from patients with a history of breast cancer and compare it to that from patients without a history of breast cancer. A retrospective chart review of pathology records on patients that underwent reduction mammoplasty from 2006 to 2012 generated 179 cases. Laterality, specimen weight, number of blocks submitted and presence of APL were recorded and analyzed. We defined APL as invasive carcinoma, ductal (DCIS) or lobular carcinoma in situ, atypical ductal or lobular hyperplasia (ADH or ALH), and flat epithelial atypia (FEA). The presence of papillomas, radial scars and fibroadenomas were also recorded. At least 1 APL was identified in 23 (12.8%) of 179 specimens including invasive lobular carcinoma (n = 3), DCIS (n = 1), ADH/FEA (n = 9) and lobular carcinoma in situ/ALH (n = 10). The most common APL in this cohort was lobular neoplasia (5.6%) followed by ADH and FEA (5.0%). Invasive carcinoma and DCIS was identified in 2.3% of this cohort. In conclusion, the frequency of detection of APLs in patients with history of breast cancer is significantly higher than that in patients without history of breast cancer (12.8% versus 4.3%). Our data assessed the prevalence of APLs in this setting and, therefore, provide new information on decision-making for contralateral breast reduction in patients with history of breast cancer.
OBJECTIVES - Syndecan-1 expression is decreased in diverse tumor types but remains controversial in breast carcinomas. The goal of the study was to examine syndecan-1 expression in breast carcinoma and its prognostic significance.
METHODS - The epithelial expression of syndecan-1 was examined in tissue microarrays constructed from 62 consecutive breast carcinoma cases diagnosed between 1997 and 2004 with distant organ metastasis and 10 consecutive control cases (breast carcinoma with no distant metastasis after at least 8 years of follow-up). The prognostic significance of syndecan-1 was estimated by utilizing a Cox proportional hazards regression model.
RESULTS - Among tumors with distant metastasis, syndecan-1 expression was significantly associated with a higher histologic grade and inversely related to hormonal receptor status. The HER2 subtype and triple-negative carcinomas exhibited markedly higher syndecan-1 levels than those of luminal subtypes, while the latter remained significantly higher than nonmetastatic control cases. Furthermore, high syndecan-1 expression had a negative impact on both overall and disease-free survival rates.
CONCLUSIONS - These findings suggest that syndecan-1 may regulate breast cancer cell behavior and thus deserves further investigation to ascertain its potential as a therapeutic target, especially in metastatic, triple-negative carcinomas.
Atypical proliferative lesions (APLs) are occasionally found in breast reduction specimens. The aim of the study was to investigate the prevalence of APL in reduction mammoplasty specimens from patients who were treated mainly for macromastia. A retrospective medical record review of pathology records on patients who underwent reduction mammoplasty from 2006 to 2012 generated 2498 cases. The sole exclusion criterion was a history of invasive and/or ductal carcinoma in situ (DCIS). Laterality, specimen weight, number of blocks submitted, and presence of APL were recorded and analyzed. We defined APL as invasive carcinoma, DCIS or lobular carcinoma in situ, atypical ductal (ADH) or lobular hyperplasia, and flat epithelial atypia (FEA). The presence of papillomas, radial scars, and fibroadenomas was also recorded. At least 1 APL was identified in 107 (4.3%) of 2498 reduction mammoplasty specimens including invasive duct carcinoma (n = 2), DCIS (n = 4), ADH/FEA (n = 47), and lobular carcinoma in situ/atypical lobular hyperplasia (n = 54). One hundred four (97%) of the 107 patients underwent bilateral, and 3 (3%) underwent unilateral reductions. In conclusion, the frequency of detection of APLs in patients with no history of breast cancer is low (4.3%). Detection of invasive and DCIS lesions is extraordinarily low at 0.2%. The most common APL is lobular neoplasia (2.2%), whereas ADH and FEA are seen in 1.9%. Our findings provide data on the distribution of these lesions in this setting, as well as some insight into their prevalence in the general population. A protocol for submitting tissues from these specimens is also proposed.
Copyright © 2013 Elsevier Inc. All rights reserved.
Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.
BACKGROUND - Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.
METHODS - MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR-positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed.
RESULT - For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple-negative (60%) and HER2-positive (62%) subtypes.
CONCLUSIONS - The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response.
Copyright © 2013 American Cancer Society.
BACKGROUND - Circulating estrogens are associated with increased breast cancer risk, yet the role of estrogen metabolites in breast carcinogenesis remains unclear. This combined analysis of 5 published studies evaluates urinary 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and their ratio (2:16α-OHE1) in relation to breast cancer risk.
METHODS - Primary data on 726 premenopausal women (183 invasive breast cancer cases and 543 controls) and 1,108 postmenopausal women (385 invasive breast cancer cases and 723 controls) were analyzed. Urinary estrogen metabolites were measured using enzyme linked immunosorbent assays. Study-specific and combined multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated based on tertiles of estrogen metabolites. Multinomial logistic regression models were fit according to hormone receptor status.
RESULTS - Higher premenopausal 2:16α-OHE1 was suggestive of reduced breast cancer risk overall (study-adjusted ORIIIvsI=0.80; 95% CI: 0.49-1.32) and for estrogen receptor negative (ER-) subtype (ORIIIvsI=0.33; 95% CI: 0.13-0.84). Among postmenopausal women, 2:16α-OHE1 was unrelated to breast cancer risk (study-adjusted ORIIIvsI=0.93; 95% CI: 0.65-1.33); however, the association between 2-OHE1 and risk varied by body mass index (p-interaction=0.003).
CONCLUSIONS - Premenopausal urinary 2:16α-OHE1 may play a role in breast carcinogenesis; however, larger studies are needed. Our findings do not support reduced breast cancer risk with higher postmenopausal 2:16α-OHE1 overall, although obesity may modify associations with 2-OHE1.