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HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women.

ABSTRACT: BACKGROUND:Breast cancer in very young women (BCVY) defined as <35 years old, presents with different molecular biology than in older patients. High HDAC5 expression has been associated with poor prognosis in breast cancer (BC) tissue. We aimed to analyze HDAC5 expression in BCVY and older patients and their correlation with clinical features, also studying the potential of HDAC5 inhibition in BC cell lines. METHODS:HDAC5 expression in 60 BCVY and 47 older cases were analyzed by qRT-PCR and correlated with clinical data. The effect of the HDAC5 inhibitor, LMK-235, was analyzed in BC cell lines from older and young patients. We performed time and dose dependence viability, migration, proliferation, and apoptosis assays. RESULTS:Our results correlate higher HDAC5 expression with worse prognosis in BCVY. However, we observed no differences between HDAC5 expression and pathological features. Our results showed greatly reduced progression in BCVY cell lines and also in all triple negative subtypes when cell lines were treated with LMK-235. CONCLUSIONS:In BCVY, we found higher expression of HDAC5. Overexpression of HDAC5 in BCVY correlates with lower survival rates. LMK-235 could be a potential treatment in BCVY.

SUBMITTER: Oltra SS

PROVIDER: S-EPMC7072585 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women.

Oltra Sara S SS Cejalvo Juan Miguel JM Tormo Eduardo E Albanell Marta M Ferrer Ana A Nacher Marta M Bermejo Begoña B Hernando Cristina C Chirivella Isabel I Alonso Elisa E Burgués Octavio O Peña-Chilet Maria M Eroles Pilar P Lluch Ana A Ribas Gloria G Martinez María Teresa MT

Cancers 20200210 2

<h4>Background</h4>Breast cancer in very young women (BCVY) defined as <35 years old, presents with different molecular biology than in older patients. High <i>HDAC5</i> expression has been associated with poor prognosis in breast cancer (BC) tissue. We aimed to analyze <i>HDAC5</i> expression in BCVY and older patients and their correlation with clinical features, also studying the potential of HDAC5 inhibition in BC cell lines.<h4>Methods</h4><i>HDAC5</i> expression in 60 BCVY and 47 older cas ...[more]

PMID: 32050699

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Project description:BACKGROUND: Breast cancer is rarely diagnosed in very young women (35 years old or younger), and it often presents with distinct clinical-pathological features related to a more aggressive phenotype and worse prognosis when diagnosed at this early age. A pending question is whether breast cancer in very young women arises from the deregulation of different underlying mechanisms, something that will make this disease an entity differentiated from breast cancer diagnosed in older patients. METHODS: We performed a comprehensive study of miRNA expression using miRNA Affymetrix2.0 array on paraffin-embedded tumour tissue of 42 breast cancer patients 35 years old or younger, 17 patients between 45 and 65 years old and 29 older than 65 years. Data were statistically analyzed by t-test and a hierarchical clustering via average linkage method was conducted. Results were validated by qRT-PCR. Putative targeted pathways were obtained using DIANA miRPath online software. RESULTS: The results show a differential and unique miRNA expression profile of 121 miRNAs (p-value <0.05), 96 of those with a FDR-value <0.05. Hierarchical clustering grouped the samples according to their age, but not by subtype nor by tumour characteristics. We were able to validate by qRT-PCR differences in the expression of 6 miRNAs: miR-1228*, miR-3196, miR-1275, miR-92b, miR-139 and miR-1207. Moreover, all of the miRNAs maintained the expression trend. The validated miRNAs pointed out pathways related to cell motility, invasion and proliferation. CONCLUSIONS: The study suggests that breast cancer in very young women appears as a distinct molecular signature. To our knowledge, this is the first time that a validated microRNA profile, distinctive to breast cancer in very young women, has been presented. The miRNA signature may be relevant to open an important field of research in order to elucidate the underlying mechanism in this particular disease, which in a more clinical setting, could potentially help to identify therapeutic targets in this particular set of patients.

Project description:PurposeOur understanding of breast cancer in very young women (≤35 years old) remains limited. We aimed to assess the clinicopathological characteristics, molecular subtype, and treatment distribution and prognosis of these young patients compared with patients over 35 years.MethodsWe retrospectively analyzed non-metastatic female breast cancer cases treated at three Chinese academic hospitals between January 1, 2008, and December 31, 2018. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between different age groups and stratified with distinct molecular subtypes.ResultsA total of 11,671 women were eligible for the final analyses, and 1,207 women (10.3%) were ≤35 years at disease onset. Very young breast cancer women were more likely to be single or childless, have higher-grade disease, have more probability of lymphovascular invasion (LVI) in tumor and triple-negative subtype, and be treated by lumpectomy, chemotherapy especially more anthracycline- and paclitaxel-based chemotherapy, endocrine therapy plus ovarian function suppression (OFS), anti-HER2 therapy, and/or radiotherapy than older women (P < 0.05 for all). Very young women had the lowest 5-year LRFS and DFS among all age groups (P < 0.001 for all). When stratified by molecular subtype, very young women had the worst outcomes vs. women from the 35~50-year-old group or those from >50-year-old group for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) subtype, including LRFS, DFS, and OS (P < 0.05 for all). In terms of LRFS and DFS, multivariate analyses showed similar results among the different age groups.ConclusionOur study demonstrated that very young women with breast cancer had higher-grade tumors, more probability of LVI in tumor, and more triple-negative subtype, when compared with older patients. They had less favorable survival outcomes, especially for patients with the HR+/HER2- subtype.

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HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women.

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HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women.

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