Selective Down-Regulation of Vitamin D Receptor Expression Is Associated with Snail-Induced Epithelial to Mesenchymal Transition in Breast Cancer Stem-Like Cells.

Abstract Background The small GTP-binding protein Rab31 plays an important role in the modulation of tumor biological-relevant processes, including cell proliferation, adhesion, and invasion. As an underlying mechanism, Rab31 is presumed to act as a molecular switch between a more proliferative and an invasive phenotype. This prompted us to analyze whether Rab31 overexpression in breast cancer cells affects expression of genes involved in epithelial-to-mesenchymal transition (EMT)-like processes when compared to Rab31 low-expressing cells. Methods Commercially available profiler PCR arrays were applied to search for differentially expressed genes in Rab31 high- and low-expressing CAMA-1 breast cancer cells. Differential expression of selected candidate genes in response to Rab31 overexpression in CAMA-1 cells was validated by independent qPCR and protein assays. Results Gene expression profiling of key genes involved in EMT, or its reciprocal process MET, identified 9 genes being significantly up- or down-regulated in Rab31 overexpressing CAMA-1 cells, with the strongest effects seen for TGFB1, encoding TGF-ß1 (> 25-fold down-regulation in Rab31 overexpressing cells). Subsequent validation analyses by qPCR revealed a strong down-regulation of TGFB1 mRNA levels in response to increased Rab31 expression not only in CAMA-1 cells, but also in another breast cancer cell line, MDA-MB-231. Using ELISA and Western blot analysis, a considerable reduction of both intracellular and secreted TGF-ß1 antigen levels was determined in Rab31 overexpressing cells compared to vector control cells. Furthermore, reduced TGF-ß activity was observed upon Rab31 overexpression in CAMA-1 cells using a sensitive TGF-ß bioassay. Finally, the relationship between Rab31 expression and the TGF-ß axis was analyzed by another profiler PCR array focusing on genes involved in TGF-ß signaling. We found 12 out of 84 mRNAs significantly reduced and 7 mRNAs significantly increased upon Rab31 overexpression. Conclusions Our results demonstrate that Rab31 is a potent modulator of the expression of TGF-ß and other components of the TGF-ß signaling pathway in breast cancer cells.

Download Full-text

Natural Bioactive Compounds as Emerging Therapeutic Molecules against Breast Cancer: Emphasis on the Role of Phytoestrogens

Current Drug Targets ◽

10.2174/1389450121999201109215341 ◽

2020 ◽

Vol 21 ◽

Author(s):

Anisha Sathyan M. ◽

Asifa K. P. ◽

Arunaksharan Narayanankutty

Keyword(s):

Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Receptor Expression ◽

Cancer Proliferation ◽

Mesenchymal Transition ◽

Drug Candidates ◽

Drug Molecules ◽

Thomson Reuters ◽

Estrogenic Potential

Background:: Breast cancer is the leading form of cancer in women, which is also hormone-dependent. Depend-ing on the receptor expression these cancers are subdivided to different forms; among the receptors, estrogen, progesterone, and Her2 are important. Targeting breast cancer (BC) has been difficult due to their varied nature; however, various Phyto-compounds, especially those are having estrogen-like properties, has been proven to be effective. Objective:: The present review is aimed to provide a detailed description of various Phytocompounds inhibiting breast cancer proliferation and progression; emphasize has been given to the role of phytoestrogens with their molecular mechanism of action. Methods:: The data were collected from reputed databases such as PubMed/Medline, Web of Science, Science Direct, Eu-rekaselect etc. Data on the phytoestrogens were collected using individual names and “phytoestrogens” as keywords. Arti-cles published in journals, which are not indexed by Thomson Reuters (SCI/SCIE/ESCI) are omitted. Results:: Natural products are important drug candidates against multiple forms of breast cancer. In addition to the initiation and proliferation events, these molecules inhibit epithelial to mesenchymal transition (EMT) and metastasis of BC. Phy-toestrogens are an important class of compounds which has known estrogenic potential; studies have also indicated the anticancer potentials of these molecules in cell culture and animal models of BC. Conclusion:: Natural plant compounds, especially, phytoestrogens are promising anti-breast cancer agents by inducing cell cycle arrest, apoptosis and autophagy-mediated cell death. However, more clinical studies are necessary to up these mole-cules are commercial drug molecules.

Download Full-text

The role of miR200c in leptin-mediated triple-negative breast cancer progression to an epithelial-to-mesenchymal transition.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12548 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12548-e12548

Author(s):

Lucas Wang ◽

Brittany Harlow ◽

Laura Bowers ◽

Stephen Hursting ◽

Linda A deGraffenried ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Leptin Receptor ◽

Triple Negative ◽

Receptor Expression ◽

Obese Women ◽

Mesenchymal Transition

e12548 Background: Almost 40% of women with breast cancer are obese at diagnosis. Obesity is associated with a worse prognosis in triple negative breast cancer (TNBC). Preclinical studies have shown that leptin is an important factor associated with TNBC by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). Transcription factors SNAIL, TWIST and ZEB are critical components in enhancing EMT in cancer cells. The specific mechanism(s) by leptin regulates SNAIL, TWIST and ZEB expression remain unclear, limiting the development of effective interventions to improve outcomes in obese TNBC patients. Recent studies have demonstrated that miR200c, downstream of leptin receptor signaling, regulates the expression of SNAIL1, TWIST and ZEB. We will test the hypothesis that leptin contributes to obesity-induced EMT/CSC in TNBC through modulation of miR200c. Methods: Ob-R (leptin receptor) expression was suppressed in TNBC MDA-MB-231 and E-Wnt cells using shRNA (Ob-R null). Ob-R and Ob-R null cells were exposed to sera pooled from lean or obese women, as well as lean sera supplemented with leptin, after which expression of SNAIL, TWIST, ZEB and miR200c was measured by qPCR, while activation of the JAK-STAT pathway was assessed by Western blotting. Results: TNBC cells exposed to obese and high leptin conditions demonstrated increased expression of EMT markers compared to levels expressed under lean conditions. The Ob-R WT and null cells were used to determine the specific role of leptin signaling in regulating expression of SNAIL, TWIST and ZEB through miR200c. Conclusions: Both obese and high leptin conditions result in increased expression of EMT regulators, suggesting that effective targeting of this pathway may provide clinical benefit in the obese breast cancer patient. Elucidating the specific mediators of this pathway will guide development of novel and more potent medical therapies.

Download Full-text

Vitamin D regulates CXCL12/CXCR4 and epithelial-to-mesenchymal transition in a model of breast cancer metastasis to lung

Endocrinology ◽

10.1210/endocr/bqab049 ◽

2021 ◽

Author(s):

Jiarong Li ◽

Aimée-Lee Luco ◽

Anne Camirand ◽

René St-Arnaud ◽

Richard Kremer

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Vitamin D Deficiency ◽

Mammary Cancer ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Lung Metastases ◽

Dietary Vitamin ◽

Mesenchymal Transition ◽

Primary Mammary Tumor

Abstract Vitamin D deficiency is associated with poor cancer outcome in humans, and administration of vitamin D or its analogs decreases tumor progression and metastasis in animal models. Using the mouse MMTV-PyMT model of mammary cancer, we previously demonstrated a significant acceleration of carcinogenesis in animals on a low vitamin D diet and a reduction in spontaneous lung metastases when mice received vitamin D through perfusion. We investigate here the action mechanism for vitamin D in lung metastasis in the same non-immunodeficient model and demonstrate it involves the control of epithelial to mesenchymal transition as well as interactions between chemokine CXCL12 and its receptor CXCR4. In vitro, 10 -9M vitamin D treatment modifies the phenotype of MMTV-PyMT primary mammary tumor cells and significantly decreases their invasiveness and mammosphere formation capacity by 40 and 50% respectively. Vitamin D treatment also inhibits p-STAT3, Zeb1 and vimentin by 52%, 75% and 77% respectively, and increases E-cadherin by 87%. In vivo, dietary vitamin D deficiency maintains high levels of Zeb1 and p-STAT3 in cells from primary mammary tumors, and increases CXCL12 expression in lung stroma by 64%. In lung metastases, vitamin D deficiency increases CXCL12/CXCR4 co-localization by a factor of 2.5. These findings indicate an involvement of vitamin D in mammary cancer ”seed” (primary tumor cell) and ”soil” (metastatic site), and link vitamin D deficiency to epithelial-to-mesenchymal transition (EMT), CXCL12/CXCR4 signaling and accelerated metastasis, suggesting vitamin D-repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing spread to distant organs.

Download Full-text

Vitamin D pathway related polymorphisms and vitamin D receptor expression in breast cancer

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000615 ◽

2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Issam Francis ◽

Noora AlAbdali ◽

Kusum Kapila ◽

Bency John ◽

Rabeah Abbas Al-Temaimi

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Vitamin D Receptor ◽

Receptor Expression ◽

Low Grade ◽

Cytoplasmic Expression ◽

Cancer Pathogenesis ◽

Common Genetic Variants

Abstract. Vitamin D deficiency is an emerging risk factor for breast cancer suggesting its role in breast cancer pathogenesis. Recent evidence suggests vitamin D receptor (VDR) expression is a prognosis predictor in breast cancer. We set out to determine the status of VDR expression in histologically characterized breast cancers, and whether common genetic variants modify VDR expression in breast cancer. One-hundred and twenty Kuwaiti female breast cancer fixed tissues were assessed for VDR expression to identify the level and location of its expression by immunohistochemistry. VDR variants (rs731236, rs2228570), and vitamin D binding protein ( VDBP) variants (rs4588, rs7041) genotypes were ascertained in breast cancer specimens using Taqman genotyping assays. VDR nuclear expression correlated with low grade tumors (p = 0.01), whereas cytoplasmic expression correlated with lymph node positive tumors (p = 0.03). Absence of VDR expression was a marker for high-grade dedifferentiated tumors (p = 0.01). VDBP rs7041 associated with breast cancer risk (OR 1.92, 95% CI: 1.34 – 2.73; p = 0.0004), and VDR rs2228570 correlated with increased VDR cytoplasmic expression (p < 0.0001). In conclusion, VDR expression is altered in breast cancer confirming its involvement in breast cancer progression. Genetic factors appear to play a role in breast cancer risk, and may modify tumor sensitization to vitamin D.

Download Full-text