BRCA1-associated Breast Carcinomas Research Articles

Modeling malignancies using induced pluripotent stem cells: from chronic myeloid leukemia to hereditary cancers

Over the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate induced pluripotent stem cells (iPSCs) from several types of primary CML cells and to generate progenitors and differentiated cells with variable efficiency. Although these experiments have brought some new insights in the understanding of CML pathophysiology, the ultimate goal of generating induced leukemic stem cells (LSCs) with long-term multilineage potential has not yet been demonstrated. Experiments under way will determine whether additional signaling events are required to induce the emergence of bona fide LSCs. However, iPSC modeling offers the unique possibility to generate pluripotent cells harboring cancer-predisposing mutations using patient-derived noncancerous cells, as has been shown in Li-Fraumeni syndrome, BRCA-1 associated breast carcinomas, or RET-mutated medullary thyroid carcinomas. In these conditions, mutated iPSCs can then be used to study the mutational history that precedes the appearance of the malignant transformation and to develop novel drug-screening strategies. The ability to induce a successful differentiation program toward the tissue in which a given cancer develops or to generate tissue-specific cancer organoids in which the full oncogenic potential can be revealed remains a major challenge in the field. Similarly, in hematological malignancies, a significant hurdle remains due to the lack of adequate technology to induce the emergence of leukemic cells that resemble LSCs, which hinders our ability to study the mechanisms of therapy resistance.

Expression of steroids and HER2-neu receptors in breast tumors associated with BRCA1 gene mutations

e22223 Background: Hereditary breast carcinomas that are attributable to BRCA1 mutations have their own morphological and immunohistochemical characteristics. This study was aimed to analyze the level of expression of steroids (estrogen and progesterone) and HER2-neu receptors in BRCA1 associated breast cancer. Methods: DNA patterns from 264 patients with hereditary breast cancers (breast cancer diagnosed at the age under 40; bilateral breast cancer; combination of breast and ovarian cancers; 2 and more breast cancers in blood relatives). All the patients were residents of the Altai Territory. BRCA1 gene mutations were registered in 34 patients (12.9%): 5382insC gene mutation - in 28 patients; 300A/C - in 2 patients; 4153del - in 3 patients; 185del - in 1 patient. The frequency of the BRCA1 5382insC allele mutation was 7.3; 300A/C - 0.52; 4153del - 0.26; 185del - 0.83. Immunohistochemical characteristics of BRCA1-associated breast tumors tissue from these patients were investigated. Results: 32 BRCA1-associated breast carcinomas were estrogen receptor- negative; 1 - week positive (H-score 50–100); 1 - moderate positive (H- score 100–200). 33 BRCA1-associated breast carcinomas were progesterone receptor- negative; 1 - positive (H-score 200 and more). HER2-negative were 31 BRCA1-associated breast carcinomas; 2 were week positive (HER2-neu +); 1 - was moderate positive (HER2-neu ++). Conclusion: BRCA1-associated beast carcinomas have been found to be more frequently estrogen receptor-, progesterone receptor-, and HER2- negative. These data show that hereditary breast cancer associated with BRCA1 gene mutations poses poor prognosis. No significant financial relationships to disclose.

Platinum Sensitivity in a BRCA1 Mutation Carrier with Advanced Breast Cancer

Although BRCA1-associated breast carcinomas are frequently detected in nodal-negative stage, they typically present with an aggressive histopathological phenotype that is reflected by a poor prognosis and an increased risk for distant metastatic spread. Recent in vitro data suggest a high sensitivity of BRCA1-associated carcinomas to platinum-based chemotherapy and a lower sensitivity to anthracyclines and taxanes. This is explained by the key role of BRCA1 in DNA double-strand repair via homologous recombination, thereby leading to a higher sensitivity to DNA intercalating agents, such as platinum. Here we present the case of a woman suffering from BRCA1-associated metastatic breast carcinoma that was resistant to docetaxel, but responded strongly to cisplatin-containing chemotherapy. This supports the rationale of ongoing clinical studies.

Triple negative, basal-like and BRCA1-associated breast cancers – what’s the difference and should anyone care?

Breast carcinoma is common in women and forms an integral part of the BRCA familial cancer syndromes. As breast cancer is considered a heterogeneous disease, clinicians have traditionally relied on clinical and morphologic findings, as well as hormone receptor/HER-2 status for prognostic and predictive categorisation of tumours. Recently, breast cancer subclassification has been aided by the discovery of various gene expression profiles, compiled after simultaneous examination of multiple tumour biomarker genes. Basal-like breast cancer was delineated using this methodology and demonstrates significant overlap with so-called triple negative and BRCA1-associated breast carcinomas. This article describes the pathology and biology of these three groups of tumours and examines the relationship between them. Therapeutic implications are also briefly discussed.

Aromatase, CYP1B1 and Fatty Acid Synthase Expression in Breast Tumors of BRCA1 Mutation Carriers

Numerous experimental evidence suggest that BRCA1-associated breast carcinomas may have distinct endocrine and metabolic features, however these peculiarities are poorly evaluated in clinical settings. Here we comparatively analyzed for the first time aromatase, estrogen 4-hydroxylase (CYP1B1) and fatty acid synthase immunohistochemical expression in breast tumors obtained from 12 BRCA1 mutations carriers and 22 non-carriers. Aromatase expression was higher in mutation carriers than in sporadic cases (p = 0.04), which confirms the earlier results obtained in cell lines with down-regulated wild-type BRCA1 and corroborates the usage of aromatase inhibitors in such patients. No differences between study groups were found in the expression of CYP1B1 and fatty acid synthase, which does not, however, mitigate the need of further search for manifestations of the excessive genotoxic effects of estrogens and for increased lipogenesis in BRCA1 mutations carriers.

Sonographic Features of Breast Carcinoma Presenting as Masses inBRCAGene Mutation Carriers

The purpose of this study was to review the sonographic features of breast cancer gene BRCA1- and BRCA2-associated breast carcinomas in comparison with "sporadic" breast carcinomas and benign breast masses. Sonograms of 233 breast masses, including 33 BRCA-associated malignant masses (BRCA1, 15; BRCA2, 18), 148 sporadic malignant masses, and 52 benign masses, were reviewed by consensus by 2 radiologists according to American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) terminology. Most of the sporadic and BRCA1-and BRCA2-associated cancers displayed an irregular shape (91.2%, 93.3%, and 83.3%, respectively). BRCA1-associated cancers showed microlobulated margins in 53.3% versus 33.8% (sporadic) and 33.3% (BRCA2). A parallel orientation was most frequently encountered in BRCA1-associated lesions (46.7%) versus sporadic (33.8%) and BRCA2 (33.3%), whereas posterior acoustic shadowing was least frequently seen in BRCA1-associated lesions (13.3%) versus BRCA2 (16.7%) and sporadic (31.1%). Most (73.3%) of the BRCA1-associated lesions were classified as BI-RADS category 4, whereas most of the sporadic and BRCA2-associated lesions were classified as BI-RADS category 5 (66.2% and 72.2%). Sonographic features of BRCA-associated and sporadic breast carcinomas do not differ substantially. BRCA1-associated breast carcinomas trend toward less malignant sonographic characteristics, but strict application of the BI-RADS categorizations demands that they be classified as category 4 or 5.

Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas

Aims: To determine whether basal-like phenotype and vimentin and/or laminin are related in both sporadic/familial (BRCA1 or BRCA2 mutated) tumours. Methods: 230 non-familial and 28 hereditary node-negative invasive breast carcinomas...

HER-2/neu status and tumor morphology of invasive breast carcinomas in Ashkenazi women with known BRCA1 mutation status in the Ontario Familial Breast Cancer Registry.

The prevalence of BRCA1 germline mutations is greater in the Ashkenazi Jewish population than in the general North American population. The Ontario Familial Breast Cancer Registry collects clinical and family history data in familial breast carcinoma cases, and unselected Ashkenazi breast carcinomas, and acts as a tumor tissue repository. Using this resource, we examined the tumor morphology, hormone receptor status, and HER-2/neu protein overexpression in Canadian Ashkenazi breast carcinoma patients whose germline BRCA1 mutation status is known. Thirty-eight tumors from 32 BRCA1 carriers and 354 tumors from 334 noncarriers were analyzed. The tumors in BRCA1 mutation carriers were more likely to be high grade (P < 0.0001) and estrogen receptor negative (P < 0.004). There was an increased frequency of typical medullary carcinomas in mutation carriers when all tumors were analyzed. However, this difference did not remain statistically significant when only the first tumor diagnosed in each patient was included in the analysis. There was no difference in HER-2/neu protein overexpression between the two groups overall (P = 0.07). However, when the analysis was restricted to Grade III tumors, there were significantly fewer HER-2/neu-positive tumors in the mutation carriers versus noncarriers (3.1% vs. 21.5%, P = 0.012). No significant differences were found in the incidence of lymph node status, progesterone receptor status, lymphatic vessel invasion, degree of lymphocytic infiltration, or in the presence of ductal carcinoma in situ associated with the invasive tumors. Increasing awareness of the morphologic and immunophenotypic features more commonly found in BRCA1-associated breast carcinomas may lead to a wider use of these characteristics in genetic screening programs and provide further clues to their pathogenesis.

Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas

Breast cancer is one of the most common malignancies among women. The molecular mechanisms involved in breast carcinogenesis, however, remain to be elucidated. Although somatic mutation of BRCA1 is rare, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas (Yoshikawa et al., Clin. Cancer Res., 5:1249-1261, 1999), indicating its possible involvement even in sporadic breast carcinogenesis. Among the BRCA1-interactive proteins are hRAD51 (a human homologue of Escherichia coli rec A protein), BARD1 (BRCA1-associated RING domain 1) and p53, all of which are involved in DNA repair. We have analyzed the expression patterns of the hRAD51, BARD1 and p53 proteins in five breast cancer cell lines, including a BRCA1-deficient cell line, and in 179 breast cancer tissue samples from Japanese women, including 113 sporadic, 47 hereditary (i.e., BRCA1 status unknown), and 19 BRCA1-associated cases. Of the 179 breast carcinomas, fifty-four (30%) exhibited reduced hRAD51 expression, and sixty-two (35%) exhibited p53 overexpression. On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch-repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases. The overall frequency of sporadic breast carcinomas with abnormal expression of either BRCA1 or the BRCA1-interactive proteins was 67% (76/113). These results indicate that there may be an important role for the BRCA1-associated DNA-repair pathway, not only in BRCA1-associated breast carcinomas, but also in sporadic breast carcinomas.

Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2: are they prognostically different?

To review the preclinical and clinical studies relevant to the prognosis and prognostic associations of BRCA1- and BRCA2-associated breast carcinomas, with an emphasis on research methodology. Reports of relevant studies obtained from a MEDLINE search, and references from these articles, were critically reviewed. Consistent associations with both favorable (medullary or atypical medullary carcinoma) and unfavorable (high tumor grade, hormone receptor negativity, somatic p53 mutation) prognostic characteristics have been found for BRCA1-associated breast carcinomas. Inconsistent results have been demonstrated for prognostic associations of BRCA2-associated breast tumors. Clinical studies that have directly assessed the prognosis of these tumors have not shown a clear effect of BRCA1 or BRCA2 mutation, but no study has used optimal methodology. In vitro and animal model data suggest a possible influence of these mutations on response to agents that cause double-strand DNA breaks, but clinical data are limited. The elucidation of an identifiable subgroup of breast carcinomas that result from germline mutations in BRCA1 or BRCA2 may be an important step toward genotype-based understanding of prognosis and choice of therapy in this disease. However, currently there are inadequate data to support use of BRCA1 or BRCA2 status to counsel individuals regarding their prognosis or to select treatment. Well-designed studies of population-based inception cohorts of breast cancer patients, which have adequate sample size and complete follow-up, and which use objective outcome criteria and blinding of outcome assessment, are required to optimally address this question.