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1.
Biochim Biophys Acta Rev Cancer ; 1875(1): 188482, 2021 01.
Article in English | MEDLINE | ID: mdl-33260050

ABSTRACT

Carriers of BRCA1 mutations have a higher chance of developing cancers in hormone-responsive tissues like the breast, ovary and prostate, compared to other tissues. These tumors generally exhibit basal-like characters and do not express estrogen receptor (ER) or progesterone receptor (PR). Intriguingly, BRCA1 mutated breast cancers have a less favorable clinical outcome, as they will not respond to hormone therapy. BRCA1 has been reported to exhibit ligand dependent and independent transcriptional inhibition of ER-α; however, there exists a controversy on whether BRCA1 induces or inhibits ER-α expression. The mechanisms associated with resistance of BRCA1 mutated cancers to hormone therapy, as well as the tissue restriction exhibited by BRCA1 mutated tumors are still largely unknown. BRCA1 mutated tumors possess increased DNA damages and decreased genomic integrity, as BRCA1 plays a cardinal role in high fidelity DNA damage repair pathways, like homologous recombination (HR). The existence of cross regulatory signaling networks between ER-α and BRCA1 speculates a role of ER on BRCA1 dependent DDR pathways. Thus, the loss or haploinsufficiency of BRCA1 and the consequential deregulation of ER-α signaling may result in persistence of unrepaired DNA damages, eventually leading to tumorigenesis. Therefore, understanding of this cross-talk between ER-α and BRCA1, with regard to DDR, will provide critical insights to steer drug development and therapy for breast/ovarian cancers. This review discusses the mechanisms by which estrogen and ER signaling influence BRCA1 mediated DNA damage response and repair pathways in the mammalian system.


Subject(s)
BRCA1 Protein/genetics , Breast Neoplasms/genetics , Carcinogenesis/genetics , Estrogen Receptor alpha/genetics , Breast/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , DNA Damage/drug effects , DNA Repair/drug effects , DNA Repair/genetics , Female , Humans , Signal Transduction/drug effects
2.
Crit Rev Oncol Hematol ; 151: 102964, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32464482

ABSTRACT

Breast Cancer is the most predominant female cancer in developed as well as developing countries. The treatment strategies of breast cancers depends on an array of factors like age at diagnosis, menstrual status, dietary pattern, immunological response, genetic variations of the cancer cells etc. Recent technological advancements in cancer diagnosis lead to the emergence of gene expression pattern for better understanding of the tumor behavior. It has not only bolstered the prognosis, but also the early diagnosis and therapy. The accuracy in disease prognosis can be boosted when gene expression signatures are combined with traditional clinicopathological features. This review explains how the evolution of gene expression signatures for breast cancers, its advantages and future prospects. In addition, an overview of currently available gene expression signature analysis tools and consolidated information on their current status and specific benefits, that can be availed for breast cancer diagnosis are also discussed.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/therapy , Breast Neoplasms/pathology , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Prognosis , Transcriptome
3.
Carcinogenesis ; 41(5): 611-624, 2020 07 10.
Article in English | MEDLINE | ID: mdl-31219560

ABSTRACT

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of 'ß-hCG' with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates ß-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- ß-hCG relationship and unraveling etio-pathology of GTD. BRCA1 level in GTD is down-regulated due to the over-expression of DNMT3b and subsequent promoter hypermethylation, when compared to the normal placentae accompanied with its shift in localization. There is an inverse correlation of serum ß-hCG levels with BRCA1 mRNA expression. The effects of methotrexate (MTX), which is the first-line chemotherapeutic used for GTD treatment, when analyzed in comparison with plumbagin (PB) revealed that PB alone is efficient than MTX alone or MTX-PB in combination, in showing selective cytotoxicity against GTD. Interestingly, PB increases BRCA1 levels post-treatment, altering DNMT3b levels and resultant BRCA1 promoter methylation. Also, cohort study analyzed the incidence of GTD at Sree Avittom Thirunal (SAT) Hospital, Thiruvananthapuram, which points out that 11.5% of gestational trophoblastic neoplasia (GTN) cases were referred to Regional Cancer Centre, Thiruvananthapuram, for examination of breast lumps. This has lend clues to supervene the risk of GTD patients towards BRCA1-associated diseases and unveil novel therapeutic for GTD, a plant-derived naphthoquinone, PB, already reported as selectively cytotoxic against BRCA1 defective tumors.


Subject(s)
BRCA1 Protein/genetics , Chorionic Gonadotropin, beta Subunit, Human/metabolism , DNA Methylation , Gestational Trophoblastic Disease/pathology , Mutation , Placenta/metabolism , Promoter Regions, Genetic , Adult , Antineoplastic Agents/pharmacology , Apoptosis , BRCA2 Protein/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Chorionic Gonadotropin, beta Subunit, Human/genetics , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Gestational Trophoblastic Disease/drug therapy , Gestational Trophoblastic Disease/genetics , Gestational Trophoblastic Disease/metabolism , Humans , Placenta/drug effects , Placenta/pathology , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Complications/genetics , Pregnancy Complications/metabolism , Pregnancy Complications/pathology , Prognosis , Trophoblastic Neoplasms/drug therapy , Trophoblastic Neoplasms/genetics , Trophoblastic Neoplasms/metabolism , Trophoblastic Neoplasms/pathology , Tumor Cells, Cultured
4.
Sci Rep ; 8(1): 13903, 2018 09 17.
Article in English | MEDLINE | ID: mdl-30224826

ABSTRACT

It is known that Cancer Associated Fibroblast (CAFs) from the primary tumor site can accompany cancer cells to a secondary site during the process of metastasis. We hypothesize that these CAFs could be transformed to an altered cell type, which can be called as Metastasis Associated Fibroblasts (MAF) in turn can support, and convoy cancer cells for metastasis. There are no published reports that have characterized and distinguished CAFs from MAF. It is well established that some of the cancer cells within the tumor mass accumulate novel mutations prior to metastasis. Hence, we speculated that mutations in the tumor suppressor gene, BRCA1, which is already reported to induce metastasis via abnormal expression of Ezrin, Radixin and Moesin (ERM), could generate MAF. In the present study, we demonstrate for the first time that CAFs isolated from primary breast cancer tissues when co-cultured with BRCA1 mutated HCC1937 cells transform CAFs to MAF in vitro. As expected, MAF augmented proliferation, migration and invasion along with over-expression of epithelial mesenchymal transition (EMT) markers, Ezrin and CCL5, thereby facilitating metastasis. Therefore, we inhibited Ezrin and CCL5 in vitro in MAF and observed that the migration and invasion abilities of these cells were attenuated. This highlights the intriguing possibilities of combination therapy using MAF inhibitors as anti-metastatic agents along with anticancer drugs, to control the metastatic spread from primary tumor site.


Subject(s)
Breast Neoplasms/pathology , Cell Transformation, Neoplastic , Genes, BRCA1 , Neoplasm Metastasis , Breast Neoplasms/genetics , Cell Line, Tumor , Coculture Techniques , Epithelial-Mesenchymal Transition , Female , Fibroblasts/pathology , Humans
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