Browsing by Author "Mandušić, Vesna (16203425000)"

Background: Precise molecular characterization of breast cancer, especially triple negative (TNBC) as the most lethal subtype, is needed to stratify patients for the individual treatment approach. MicroRNA-205 (miR-205) has tumor-suppressive and oncogenic functions across different cancers. Therefore, miR-205 might have a different role in TNBC and estrogen receptor (ER) positive BC. Our aim was to investigate how miR-205 expression is associated with ER/progesteron receptor status, clinical parameters, pathohistological characteristics of BC, and survival of patients Methods: We determined miR-205 relative expressions in 73 primary breast tumors (50 TNBC and 23 ER+) by quantitative Real-time polymerase chain reaction (qPCR) and compared it to clinicopathological characteristics and outcome. Results: The highest levels of miR-205 were in the ER+ /PR+ group, and the lowest in the TNBC group (p = 0.009). Significantly higher levels of miR-205 were also observed in the ER+ compared with the ER-negative group, regardless of the PR status (p = 0.002). Low miR-205 expression level was associated with prognostic stage III in TNBC samples (p = 0.049). Patients who received adjuvant chemotherapy had significantly lower levels of miR-205 (p = 0.016). Patients who received hormone therapy had significantly higher levels of miR-205 (p = 0.007). The low-miR-205 patients had significantly higher 5-year survival rates (p = 0.041). Conclusion: The expression of miR-205 in BC is subtype-specific and high expression is associated with the ER+ tumors. The miR-205 expression might be a useful marker of TNBC progression. High miR-205 expression had a detrimental effect on BC patient outcome. Our results indicate that miR-205 might be utilized in clinical practice as a biomarker and an adjunct parameter for the selection of the most effective therapeutic modality. © 2022 Elsevier GmbH

Background: Precise molecular characterization of breast cancer, especially triple negative (TNBC) as the most lethal subtype, is needed to stratify patients for the individual treatment approach. MicroRNA-205 (miR-205) has tumor-suppressive and oncogenic functions across different cancers. Therefore, miR-205 might have a different role in TNBC and estrogen receptor (ER) positive BC. Our aim was to investigate how miR-205 expression is associated with ER/progesteron receptor status, clinical parameters, pathohistological characteristics of BC, and survival of patients Methods: We determined miR-205 relative expressions in 73 primary breast tumors (50 TNBC and 23 ER+) by quantitative Real-time polymerase chain reaction (qPCR) and compared it to clinicopathological characteristics and outcome. Results: The highest levels of miR-205 were in the ER+ /PR+ group, and the lowest in the TNBC group (p = 0.009). Significantly higher levels of miR-205 were also observed in the ER+ compared with the ER-negative group, regardless of the PR status (p = 0.002). Low miR-205 expression level was associated with prognostic stage III in TNBC samples (p = 0.049). Patients who received adjuvant chemotherapy had significantly lower levels of miR-205 (p = 0.016). Patients who received hormone therapy had significantly higher levels of miR-205 (p = 0.007). The low-miR-205 patients had significantly higher 5-year survival rates (p = 0.041). Conclusion: The expression of miR-205 in BC is subtype-specific and high expression is associated with the ER+ tumors. The miR-205 expression might be a useful marker of TNBC progression. High miR-205 expression had a detrimental effect on BC patient outcome. Our results indicate that miR-205 might be utilized in clinical practice as a biomarker and an adjunct parameter for the selection of the most effective therapeutic modality. © 2022 Elsevier GmbH

Purpose: In addition to Estrogen Receptor α (ERα) and Progesterone Receptor (PR), the Second Estrogen Receptor (ERβ) appears to play an important role not only in estrogen signaling, but also in the pathogenesis of cancer in estrogen dependent tissues. The existence of various isoforms and splice variants of both ERs additionally complicates elucidation of their physiological role and involvement in the process of carcinogenesis. Methods: In this study, the expression of ERβ1 mRNA (wild type of β receptor) and splice variant ERβΔ5 mRNA (which codes for truncated protein) was measured by the quantitative RT-PCR (q RT-PCR) in the 60 samples of Breast Cancer (BC) and correlated with ERα and PR protein levels and with clinical and histopathological parameters. Results: We found the inverse correlation of ERβΔ5 mRNA expression with the levels of PR and ERα proteins in the group of postmenopausal patients; we also report the lower expression of ERβ1 and ERβΔ5 mRNA in the larger tumors (>20 mm, T2, and T3) than in smaller ones (≤20 mm, T1). The decrease of ERβΔ5 mRNA expression in larger tumors is found to arise from ER-positive breast carcinomas. In addition, the portion of tumors with concomitant high expression of both transcripts matches up the known percentage of tumors resistant to endocrine therapy in patients with different ER/PR status. Conclusions: As far as we know, this is the first study in which ERβΔ5 mRNA splice variant was quantified by real-time RT-PCR in the clinical samples of breast cancer tissue. Until now, the focus of clinical reports was the level of ERβ1, ERβ2, and ERβ5 isoforms. The higher expression of ERβΔ5 mRNA is associated with the indicators of low biological aggressiveness of tumor (low tumor size within ER-positive status in our study) suggesting that the uncontrolled local tumor growth may occur as the expression of ERβΔ5 mRNA decreases in estrogen-dependent breast cancer. © 2007 Springer-Verlag.

Purpose: In addition to Estrogen Receptor α (ERα) and Progesterone Receptor (PR), the Second Estrogen Receptor (ERβ) appears to play an important role not only in estrogen signaling, but also in the pathogenesis of cancer in estrogen dependent tissues. The existence of various isoforms and splice variants of both ERs additionally complicates elucidation of their physiological role and involvement in the process of carcinogenesis. Methods: In this study, the expression of ERβ1 mRNA (wild type of β receptor) and splice variant ERβΔ5 mRNA (which codes for truncated protein) was measured by the quantitative RT-PCR (q RT-PCR) in the 60 samples of Breast Cancer (BC) and correlated with ERα and PR protein levels and with clinical and histopathological parameters. Results: We found the inverse correlation of ERβΔ5 mRNA expression with the levels of PR and ERα proteins in the group of postmenopausal patients; we also report the lower expression of ERβ1 and ERβΔ5 mRNA in the larger tumors (>20 mm, T2, and T3) than in smaller ones (≤20 mm, T1). The decrease of ERβΔ5 mRNA expression in larger tumors is found to arise from ER-positive breast carcinomas. In addition, the portion of tumors with concomitant high expression of both transcripts matches up the known percentage of tumors resistant to endocrine therapy in patients with different ER/PR status. Conclusions: As far as we know, this is the first study in which ERβΔ5 mRNA splice variant was quantified by real-time RT-PCR in the clinical samples of breast cancer tissue. Until now, the focus of clinical reports was the level of ERβ1, ERβ2, and ERβ5 isoforms. The higher expression of ERβΔ5 mRNA is associated with the indicators of low biological aggressiveness of tumor (low tumor size within ER-positive status in our study) suggesting that the uncontrolled local tumor growth may occur as the expression of ERβΔ5 mRNA decreases in estrogen-dependent breast cancer. © 2007 Springer-Verlag.

A growing body of evidence suggests a role of the von Hippel–Lindau (VHL) tumor suppressor gene in the progression of papillary thyroid carcinoma (PTC). Our previous study of VHL in PTCs showed that lower VHL expression was associated with aggressive tumor features, but we found no evidence for VHL downregulation through common genetic or epigenetic modifications. Several studies pointed to a role of microRNA-92a (miR-92a) in the regulation of VHL expression in different cancers. In the present study, we examined the expression levels of VHL mRNA and miR-92a in 42 pairs of PTCs and matched non-tumor thyroid tissues by means of quantitative RT-PCR. We explored the correlation between them and their association with clinicopathological parameters. The results revealed that both VHL and miR-92a were either up- or downregulated in PTCs compared to corresponding non-tumor tissues. On univariate analysis, lower VHL levels were significantly associated with extrathyroid spread (P = 0.022) and capsular invasion (P = 0.032). Multivariate analysis confirmed the association of low VHL with extrathyroid spread (OR 0.246, 95% CI 0.069–0.872, P = 0.038). Higher miR-92a among PTC tissues associated with the presence of nodal metastases (univariate analysis: P = 0.012; multivariate: OR 4.703, 95% CI 1.109–19.938, P = 0.036). A negative correlation between VHL and miR-92a was observed in a subgroup of PTCs having vascular invasion (P = 0.033, r = − 0.673). The data here reported demonstrate that the expression of both VHL and miR-92a is deregulated in PTC tissues and that in some PTCs they may have opposite roles. These roles, as well as their diagnostic and/or prognostic utility, remain to be clarified. © 2017, Springer Science+Business Media, LLC, part of Springer Nature.

A growing body of evidence suggests a role of the von Hippel–Lindau (VHL) tumor suppressor gene in the progression of papillary thyroid carcinoma (PTC). Our previous study of VHL in PTCs showed that lower VHL expression was associated with aggressive tumor features, but we found no evidence for VHL downregulation through common genetic or epigenetic modifications. Several studies pointed to a role of microRNA-92a (miR-92a) in the regulation of VHL expression in different cancers. In the present study, we examined the expression levels of VHL mRNA and miR-92a in 42 pairs of PTCs and matched non-tumor thyroid tissues by means of quantitative RT-PCR. We explored the correlation between them and their association with clinicopathological parameters. The results revealed that both VHL and miR-92a were either up- or downregulated in PTCs compared to corresponding non-tumor tissues. On univariate analysis, lower VHL levels were significantly associated with extrathyroid spread (P = 0.022) and capsular invasion (P = 0.032). Multivariate analysis confirmed the association of low VHL with extrathyroid spread (OR 0.246, 95% CI 0.069–0.872, P = 0.038). Higher miR-92a among PTC tissues associated with the presence of nodal metastases (univariate analysis: P = 0.012; multivariate: OR 4.703, 95% CI 1.109–19.938, P = 0.036). A negative correlation between VHL and miR-92a was observed in a subgroup of PTCs having vascular invasion (P = 0.033, r = − 0.673). The data here reported demonstrate that the expression of both VHL and miR-92a is deregulated in PTC tissues and that in some PTCs they may have opposite roles. These roles, as well as their diagnostic and/or prognostic utility, remain to be clarified. © 2017, Springer Science+Business Media, LLC, part of Springer Nature.

Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/ undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 INK4a/p14ARF genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14ARF gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14 ARF promoter. The results from the current study suggest significant impact of the p14ARF gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma. © Springer Science+Business Media New York 2013.

Liposarcoma represents the most frequent group of soft tissue sarcomas. The group can be divided into three different classes: (1) differentiated/ undifferentiated (WDLPS/DDLPS), (2) myxoid/round cell (MLPS/RCLPS) and (3) pleomorphic liposarcoma (PLS). It has become apparent that p53-p14 and Rb-p16 pathways play important roles in the pathogenesis of various sarcoma types. Molecular studies of the genes involved in these two pathways showed wide variations between the liposarcoma subtypes or even within the same subtype. We sought to examine mutational status of p53 and methylation status of p16 INK4a/p14ARF genes in primary and recurrent liposarcoma tumors. There were twelve myxoid (12/18, 66.7 %) and six pleomorphic liposarcoma (6/18, 33.3 %) samples. Immunohistochemical analysis revealed that p53 protein was overexpressed in 3/12 MLPS (25 %) and 6/6 PLS (100 %). Mutational analysis showed that 2/11 MLPS (18.2 %) and 2/6 PLS (33.3 %) contained mutated p53 gene. On the other hand, 3/18 samples (16.7 %) had methylated p16 promoter. However, the frequencies of the p14ARF gene methylation were 83.3 % (10/12) and 50 % (3/6) in myxoid and pleomorphic group, respectively. Overall, 15 out of 18 (83.3 %) samples had either p53 gene mutation or methylated p14 ARF promoter. The results from the current study suggest significant impact of the p14ARF gene methylation on the pathogenesis and progression of myxoid and to a lesser extent pleomorphic liposarcoma. Despite the limited number of samples, our study points to necessity of further investigation of p53-p14 and Rb-p16 pathways in liposarcoma. © Springer Science+Business Media New York 2013.

Background: Estrogen and progesterone receptor (ER/PR) status is an accepted predictive marker in breast cancer. It is well known that breast tumors, which are ER(+) are more likely to respond to endocrine therapy. However, certain percentage of ER(+)/PR(+) tumors do not respond to endocrine therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ERβ), as well as the existence of numerous isoforms/splice variants of both ERα and ERβ, suggests that complex regulation of estrogen action exists. In this study, we analyze does the expression of two ERβ isoforms correlates with ERα/PR status. Methods: Sixty samples of primary operable breast carcinomas were analyzed for ERα and PR protein levels and for mRNA expression of two ERβ isoforms (ERβ1 and ERβΔ5). ERα and PR proteins were measured by classical biochemical techniques, and ERβ mRNAs were measured by real-time RT-PCR. Results: Tumors are divided in three groups according to relative level of mRNA for ERβ1 and ERβΔ5. We found that there is no correlation of ERβ1 mRNA expression with ERα and PR protein levels. We confirmed the existence of inverse correlation of ERβΔ5 with PR and of ERβΔ5 with ERα in the group of postmenopausal patients. In the subsets of tumors defined by ERα/PR status, we found that percentage of tumors, which concomitantly expressed high levels of both transcripts, are parallel with those that do not response to tamoxifen treatment. Conclusion: Inverse correlation of ERα with ERβΔ5 and PR with ERβΔ5 isoform suggests that ERβΔ5 may have inhibitory effect on ERα activity in postmenopausal patients. In addition, we point out that determination of expression profiles of ERα and ERβ isoforms in the defined groups of patient are necessary for elucidating its involvement in endocrine resistance. © 2006, Institute of Oncology Sremska Kamenica.