Molecular Subtype-Specific Expression of MicroRNA-29c in Breast Cancer Is Associated with CpG Dinucleotide Methylation of the Promoter

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.

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Cadmium, Selenium and Breast Cancer Risk by Molecular Subtype Among Women from Northern Mexico

Exposure and Health ◽

10.1007/s12403-021-00393-w ◽

2021 ◽

Author(s):

Elodia Rojas-Lima ◽

Stephen J. Rothenberg ◽

Brenda Gamboa-Loira ◽

Ángel Mérida-Ortega ◽

Mariano E. Cebrián ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Molecular Subtype ◽

Northern Mexico ◽

Cadmium Selenium

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Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Cancers ◽

10.3390/cancers13020259 ◽

2021 ◽

Vol 13 (2) ◽

pp. 259

Author(s):

Monish Ram Makena ◽

Myungjun Ko ◽

Donna Kimberly Dang ◽

Rajini Rao

Keyword(s):

Breast Cancer ◽

Secretory Pathway ◽

Histone Deacetylase Inhibitors ◽

Epithelial To Mesenchymal Transition ◽

Molecular Subtype ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Tumor Cell Migration ◽

Canonical Wnt

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

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Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Cancers ◽

10.3390/cancers13061246 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1246

Author(s):

Marta Sanz-Álvarez ◽

Ion Cristóbal ◽

Melani Luque ◽

Andrea Santos ◽

Sandra Zazo ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Molecular Subtype ◽

Molecular Target ◽

Prognostic Impact ◽

Breast Cancer Patients ◽

Bet Inhibitors ◽

Brd4 Inhibition ◽

Bet Protein

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

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Breast cancer brain metastases: Molecular subtype, treatment and survival

Breast Disease ◽

10.3233/bd-160237 ◽

2016 ◽

Vol 36 (4) ◽

pp. 133-141 ◽

Cited By ~ 2

Author(s):

Jennifer A. Crozier ◽

Lauren F. Cornell ◽

Bhupendra Rawal ◽

Edith A. Perez

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Molecular Subtype ◽

Breast Cancer Brain Metastases

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Laboratory indicators predict axillary nodal pathologic complete response after neoadjuvant therapy in breast cancer

Future Oncology ◽

10.2217/fon-2020-1231 ◽

2021 ◽

Author(s):

Peng Chen ◽

Tong Zhao ◽

Zhao Bi ◽

Zhao-Peng Zhang ◽

Li Xie ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Neoadjuvant Therapy ◽

Predictive Factors ◽

Molecular Subtype ◽

Treatment Options ◽

Pathologic Complete Response ◽

Complete Response ◽

Breast Cancer Patients ◽

Logistic Analysis

The purpose was to integrate clinicopathological and laboratory indicators to predict axillary nodal pathologic complete response (apCR) after neoadjuvant therapy (NAT). The pretreatment clinicopathological and laboratory indicators of 416 clinical nodal-positive breast cancer patients who underwent surgery after NAT were analyzed from April 2015 to 2020. Predictive factors of apCR were examined by logistic analysis. A nomogram was built according to logistic analysis. Among the 416 patients, 37.3% achieved apCR. Multivariate analysis showed that age, pathological grading, molecular subtype and neutrophil-to-lymphocyte ratio were independent predictors of apCR. A nomogram was established based on these four factors. The area under the curve (AUC) was 0.758 in the training set. The validation set showed good discrimination, with AUC of 0.732. In subtype analysis, apCR was 23.8, 47.1 and 50.8% in hormone receptor-positive/HER2-, HER2+ and triple-negative subgroups, respectively. According to the results of the multivariate analysis, pathological grade and fibrinogen level were independent predictors of apCR after NAT in HER2+ patients. Except for traditional clinicopathological factors, laboratory indicators could also be identified as predictive factors of apCR after NAT. The nomogram integrating pretreatment indicators demonstrated its distinguishing capability, with a high AUC, and could help to guide individualized treatment options.

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