Aminosteroid RM-581 Decreases Cell Proliferation of All Breast Cancer Molecular Subtypes, Alone and in Combination with Breast Cancer Treatments.

Breast cancer (BC) is a heterogenous disease classified into four molecular subtypes (Luminal A, Luminal B, HER2 and triple-negative (TNBC)) depending on the expression of the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal receptor 2 (HER2). The development of effective treatments for BC, especially TNBC, remains a challenge. Aminosteroid derivative RM-581 has previously shown an antiproliferative effect in multiple cancers in vitro and in vivo.

Role of Secreted Frizzled-Related Protein 1 in Early Breast Carcinogenesis and Breast Cancer Aggressiveness.

A human transcriptome array on ERα-positive breast cancer continuum of risk identified () as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of in breast carcinogenesis remains, nevertheless, not well understood.

TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer.

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC ( = 58) and non-TNBC ( = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index.

Is Carboxypeptidase B1 a Prognostic Marker for Ductal Carcinoma In Situ?

Ductal carcinoma in situ (DCIS) is considered a non-obligatory precursor for invasive ductal carcinoma (IDC). Around 70% of women with atypical ductal hyperplasia (ADH) undergo unnecessary surgery due to the difficulty in differentiating ADH from low-grade DCIS. If untreated, 14-60% of DCIS progress to IDC, highlighting the importance of identifying a DCIS gene signature.

Associations between markers of mammary adipose tissue dysfunction and breast cancer prognostic factors.

Background: Obesity fosters worse clinical outcomes in both premenopausal and postmenopausal women with breast cancer. Emerging evidence suggests that an android body fat distribution in particular is deleterious for breast cancer prognosis. The extent of adipose tissue dysfunction, especially how it relates to breast cancer prognostic factors and anthropometric measurements, has not been fully investigated.

Machine learning analysis identifies genes differentiating triple negative breast cancers.

Triple negative breast cancer (TNBC) is one of the most aggressive form of breast cancer (BC) with the highest mortality due to high rate of relapse, resistance, and lack of an effective treatment. Various molecular approaches have been used to target TNBC but with little success. Here, using machine learning algorithms, we analyzed the available BC data from the Cancer Genome Atlas Network (TCGA) and have identified two potential genes, TBC1D9 (TBC1 domain family member 9) and MFGE8 (Milk Fat Globule-EGF Factor 8 Protein), that could successfully differentiate TNBC from non-TNBC, irrespective of their heterogeneity.

Trastuzumab effects depend on HER2 phosphorylation in HER2-negative breast cancer cell lines.

The breast cancer (BC) biomarker HER2 (Human Epidermal Receptor 2) is overexpressed in 25% of BC. Only patients with HER2-positive tumors receive HER2-targeting therapies, like trastuzumab (Herceptin). However, some women with a HER2-negative BC could benefit from trastuzumab.

An isoform of AIF1 involved in breast cancer.

Background: Inflammation is a major player in breast cancer (BC) progression. Allograft-inflammatory factor-1 (AIF1) is a crucial mediator in the inflammatory response. AIF1 reportedly plays a role in BC, but the mechanism remains to be elucidated.

Transcriptional signature of lymphoblastoid cell lines of , and non- high risk breast cancer families.

Approximately 25% of hereditary breast cancer cases are associated with a strong familial history which can be explained by mutations in or and other lower penetrance genes. The remaining high-risk families could be classified as BRCAX (non-) families. Gene expression involving alternative splicing represents a well-known mechanism regulating the expression of multiple transcripts, which could be involved in cancer development.

Genome-wide methylation analysis of DNMT3B gene isoforms revealed specific methylation profiles in breast cell lines.

Aim: The goal of this study is to characterize the specific methylation profile triggered by DNMT3B protein isoforms expressed at different levels in breast cell lines.

Materials & Methods: Microarray DNA methylation data were analyzed and associated with functional genome annotation data.

Results: A large spectrum of DNMT3B3/DNMT3B2 expression ratio values was observed in parental breast cell lines.

Analysis of a FANCE Splice Isoform in Regard to DNA Repair.

The FANC-BRCA DNA repair pathway is activated in response to interstrand crosslinks formed in DNA. A homozygous mutation in 1 of the 17 Fanconi anemia (FA) genes results in malfunctions of this pathway and development of FA syndrome. The integrity of this protein network is essential for good maintenance of DNA repair process and genome stability.

Analysis of ZNF350/ZBRK1 promoter variants and breast cancer susceptibility in non-BRCA1/2 French Canadian breast cancer families.

ZNF350/ZBRK1 is a transcription factor, which associates with BRCA1 to co-repress GADD45A to regulate DNA damage repair, and the expression of ZNF350 is altered in different human carcinomas. In a previous study, we identified ZNF350 genomic variants potentially involved in breast cancer susceptibility in high-risk non-BRCA1/2 breast cancer individuals, which pointed toward a potential association for variants in the 5'-UTR and promoter regions. Therefore, direct sequencing was undertaken and identified 12 promoter variants, whereas haplotype analyses put in evidence four common haplotypes with a frequency>2%.

Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population.

The majority of genes associated with breast cancer susceptibility, including BRCA1 and BRCA2 genes, are involved in DNA repair mechanisms. Moreover, among the genes recently associated with an increased susceptibility to breast cancer, four are Fanconi Anemia (FA) genes: FANCD1/BRCA2, FANCJ/BACH1/BRIP1, FANCN/PALB2 and FANCO/RAD51C. FANCA is implicated in DNA repair and has been shown to interact directly with BRCA1.

Evaluation of the contribution of the three breast cancer susceptibility genes CHEK2, STK11, and PALB2 in non-BRCA1/2 French Canadian families with high risk of breast cancer.

Inactivating mutations of the CHEK2 and STK11 genes are responsible for Li-Fraumeni and Peutz-Jeghers syndrome, respectively, both autosomal dominant syndromes associated with an increased risk of breast cancer. The PALB2/FANCN gene encodes a nuclear partner of BRCA2 and acts as a linker between BRCA1 and BRCA2. Monoallelic PALB2 truncating mutations were shown to confer higher risk of breast cancer.

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer.

Background: The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.

Methods: In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the NBN gene in our cohort of 97 high-risk non-BRCA1 and -BRCA2 breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population.

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer.

Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes.

Mutational analysis of the breast cancer susceptibility gene BRIP1 /BACH1/FANCJ in high-risk non-BRCA1/BRCA2 breast cancer families.

The BRIP1 gene encodes a helicase interacting with BRCA1, which contributes to BRCA1-associated DNA repair function. Germ-line BRIP1 mutations affecting the helicase domain activity have been identified in early onset breast cancer patients. In addition, BRIP1 was recently identified as deficient in Fanconi anemia (FA) complementation group J.

Analysis of GADD45A sequence variations in French Canadian families with high risk of breast cancer.

GADD45A is an evolutionary conserved gene whose expression is regulated by two major tumor suppressor proteins involved in breast cancer etiology, namely, p53 and BRCA1, and which acts primarily in the control of the G2/M cell-cycle transition, apoptosis, and DNA repair. Following genotoxic stress, the p53 protein activates GADD45A transcription, whereas in absence of DNA damage, BRCA1 represses GADD45A expression through interaction with the zinc finger protein ZNF350. Moreover, BRCA1 can activate GADD45A gene expression through interactions with transcription factors binding to the gene promoter.

Genetic sequence variations and ADPRT haplotype analysis in French Canadian families with high risk of breast cancer.

The poly(ADP-ribose) polymerase (PARP/ADPRT) protein family catalyzes the synthesis of cellular poly(ADP-ribose) following DNA damage and is involved in genomic integrity by regulating cellular responses to DNA damage and apoptosis. Moreover, ADPRT inhibition contributes to a protective effect against cancer development. These findings render ADPRT an attractive candidate susceptibility gene for breast cancer, and thus the goal of this study was to evaluate the possible involvement of ADPRT sequence variations in breast cancer susceptibility.

Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families.

Our current understanding of breast cancer susceptibility involves mutations in the 2 major genes BRCA1 and BRCA2, found in about 25% of high-risk families, as well as few other low penetrance genes such as ATM and CHEK2. Approximately two-thirds of the multiple cases families remain to be explained by mutations in still unknown genes. In a candidate gene approach to identify new genes potentially involved in breast cancer susceptibility, we analyzed genomic variants in the ZBRK1 gene, a co-repressor implicated in BRCA1-mediated repression of GADD45.

Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families.

Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for approximately 25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases.

Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families.

Background: Ataxia telangiectasia-mutated and Rad3-related (ATR) is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition.