Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer

Citron, Francesca; Segatto, Ilenia; Vinciguerra, Gian Luca Rampioni; Musco, Lorena; Russo, Francesca; Mungo, Giorgia; D'Andrea, Sara; Mattevi, Maria Chiara; Perin, Tiziana; Schiappacassi, Mónica; Massarut, Samuele; Marchini, Cristina; Amici, Augusto; Vecchione, Andrea; Baldassarre, Gustavo

doi:10.1158/0008-5472.can-19-1793

Cited by 52 publications

(58 citation statements)

References 37 publications

(59 reference statements)

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“…miR-223-3p is also downregulated in HER2-overexpressing C5.2 cell line [25]. Citron et al postulated a central role for miR-223 in the control of epidermal growth factor signaling and HER2 activation, as it reduces the oncogenic potential of HER2-transformed mammary epithelial cells [26]. Moreover, activation of HER2 downregulates miR-223-3p via RB repression and E2F1 activation [26].…”

Section: Discussionmentioning

confidence: 99%

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

et al. 2020

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Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student’s T-test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(−)/PgR(+) and ER(+)/PgR(−) breast cancers. However, a trend for differing expression (p-value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(−) group demonstrated elevated levels of four miRNAs—miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p—while the ER(−)/PgR(+) tumors were enriched in another four miRNAs—miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs—miR-29c-3p—the association with the ER(+)/PgR(−) phenotype was confirmed in the TCGA cohort (p-value = 0.024; T-test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(−) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(−)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(−)/PgR(+) and ER(+)/PgR(−) tumors.

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Section: Discussionmentioning

confidence: 99%

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

et al. 2020

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“…In pancreatic cancer cells, miR‐223 promotes cancer cell proliferation and invasion by targeting PDS5B which acts as a repressor of pancreatic cancer development (Ma et al ., 2019). In breast cancer, miR‐223 functions as a repressor in the initiation or chemoresistance of breast cancer (Citron et al ., 2020; Masciarelli et al ., 2014; Pinatel et al ., 2014). Particularly, loss of miR‐223 is an early event during breast transformation (Citron et al ., 2020), and stroma derived miR‐223 inhibits tumor cell migration and invasion (Pinatel et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, miR‐223 functions as a repressor in the initiation or chemoresistance of breast cancer (Citron et al ., 2020; Masciarelli et al ., 2014; Pinatel et al ., 2014). Particularly, loss of miR‐223 is an early event during breast transformation (Citron et al ., 2020), and stroma derived miR‐223 inhibits tumor cell migration and invasion (Pinatel et al ., 2014). These studies suggest that the miR‐223/E2F1 axis plays an important role not only in blood cancer, but also in solid cancers.…”

Section: Discussionmentioning

confidence: 99%

The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

Jiang

Qian

et al. 2020

Molecular Oncology

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Cervical cancer is induced by persistent infections with high‐risk human papillomaviruses (HPVs), which produce the early protein 6 of HPVs (E6)/E7 protein that is involved in cell transformation by interacting with several oncoproteins or tumor suppressors. However, the role of noncoding RNA in mediating the pathogenesis of cervical cancer remains unclear. Here, we report that the novel signal transducer and activator of transcription 3 (STAT3)‐microRNA‐223‐3p (miR‐223)‐TGFBR3/HMGCS1 axis regulated by the E6 protein controls cervical carcinogenesis. miR‐223 was highly expressed in cervical tumor tissues, whereas TGFBR3 or HMGCS1 was significantly downregulated. miR‐223 targeted the 3′‐UTRs of TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage‐independent growth and cervical squamous cell carcinoma (CSCC) tumor growth in vitro and in vivo. The increased expression of miR‐223 was mediated by the transcription factor STAT3, whose activity was enhanced by E6 in the context of interleukin (IL)‐6 stimulation. In addition, exosomal miR‐223 derived from CSCC cells induced IL‐6 secretion by monocyte/macrophage in a coculture system in vitro, and IL‐6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR‐223 inhibitor effectively suppressed tumor growth in cell line‐derived xenograft model, suggesting that miR‐223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3‐miR‐223‐HMGCS1/TGFBR3 axis functions as a key signaling pathway in cervical cancer progression and provides a new therapeutic target.

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“…On the other hand, downregulation of miR-223 confers resistance to CDK 4/6 inhibitors in luminal BC and identifies aggressive DCIS as an early event during mammary carcinogenesis. miR-223 expression is increased in case of palbociclib therapy and is a marker of effective treatment [ 131 ].…”

Section: Mirnas and Their Role In Endocrine Resistancementioning

confidence: 99%

miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment

Kúdela

Samec

Koklesová

et al. 2020

IJMS

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Breast cancer, which is the most common malignancy in women, does not form a uniform nosological unit but represents a group of malignant diseases with specific clinical, histopathological, and molecular characteristics. The increasing knowledge of the complex pathophysiological web of processes connected with breast cancercarcinogenesis allows the development of predictive and prognostic gene expressionand molecular classification systems with improved risk assessment, which could be used for individualized treatment. In our review article, we present the up-to-date knowledge about the role of miRNAs and their prognostic and predictive value in luminal A breast cancer. Indeed, an altered expression profile of miRNAs can distinguish not only between cancer and healthy samples, but they can classify specific molecular subtypes of breast cancer including HER2, Luminal A, Luminal B, and TNBC. Early identification and classification of breast cancer subtypes using miRNA expression profilescharacterize a promising approach in the field of personalized medicine. A detection of sensitive and specific biomarkers to distinguish between healthy and early breast cancer patients can be achieved by an evaluation of the different expression of several miRNAs. Consequently, miRNAs represent a potential as good diagnostic, prognostic, predictive, and therapeutic biomarkers for patients with luminal A in the early stage of BC.

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Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer

Cited by 52 publications

References 37 publications

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

The STAT3‐miR‐223‐TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma

miRNA Expression Profiles in Luminal A Breast Cancer—Implications in Biology, Prognosis, and Prediction of Response to Hormonal Treatment

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