Molecular and Cellular Mechanisms of Cancers: Breast Cancer

Topic Information

Dear Colleagues,

Breast cancer is the most common cancer in women. Different types of breast cancer show considerable variability in prognosis and treatment modalities based on cellular targets. Despite advances in diagnostics and improvements in treatment options, breast cancer is a leading cause of cancer-associated deaths. Triple-negative breast cancer (TNBC) often lacks the expression of estrogen receptor α (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for 15–20% of all diagnosed breast cancers. This aggressive subtype can metastasize to the lungs and brain, leading to significant patient mortality. Thus, it is imperative to uncover innovative approaches to combat TNBC and improve patient survival. We are facing many challenging questions in TNBC. For example, metastasis to distant organs heavily involves interaction between tumor cells and the microenvironment, both at the primary and metastatic sites. We need to know how the tumor microenvironment contributes to immunotherapy resistance. The aim of this issue is to bring researchers and clinicians together to explore challenging issues and solutions regarding TNBC. Special considerations should be given to new findings of TNBC metastasis, chemotherapy, immunotherapy, tumor metabolism, and tumor microenvironment. We expect that this Topic will provide new findings into TNBC and facilitate innovative approaches to treat patients.

Dr. Yi Huang
Dr. Qun Zhou
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Cells cells	5.1	9.9	2012	17 Days	CHF 2700
Journal of Molecular Pathology jmp	-	-	2020	26.5 Days	CHF 1000
Organoids organoids	-	-	2022	19.3 Days	CHF 1000
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700

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Published Papers (12 papers)

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Open AccessArticle

Human Breast Cancer Cell Lines Differentially Modulate Signaling from Distant Microenvironments, Which Reflects Their Metastatic Potential

by Ramon Ocadiz-Ruiz, Joseph T. Decker, Kate Griffin, Zoey M. Tan, Nishant K. Domala, Jacqueline S. Jeruss and Lonnie D. Shea

Cancers 2024, 16(4), 796; https://doi.org/10.3390/cancers16040796 - 15 Feb 2024

Cited by 2 | Viewed by 1721

Abstract

Metastasis is the stage at which the prognosis substantially decreases for many types of cancer. The ability of tumor cells to metastasize is dependent upon the characteristics of the tumor cells, and the conditioning of distant tissues that support colonization by metastatic cells. [...] Read more.

Metastasis is the stage at which the prognosis substantially decreases for many types of cancer. The ability of tumor cells to metastasize is dependent upon the characteristics of the tumor cells, and the conditioning of distant tissues that support colonization by metastatic cells. In this report, we investigated the systemic alterations in distant tissues caused by multiple human breast cancer cell lines and the impact of these alterations on the tumor cell phenotype. We observed that the niche within the lung, a common metastatic site, was significantly altered by MDA-MB-231, MCF7, and T47 tumors, and that the lung microenvironment stimulated, to differing extents, an epithelial-to-mesenchymal transition (EMT), reducing proliferation, increasing transendothelial migration and senescence, with no significant impact on cell death. We also investigated the ability of an implantable scaffold, which supports the formation of a distant tissue, to serve as a surrogate for the lung to identify systemic alterations. The scaffolds are conditioned by the primary tumor similarly to the lung for each tumor type, evidenced by promoting a pro-EMT profile. Collectively, we demonstrate that metastatic and non-metastatic breast cancers condition distant tissues, with distinct effects on tumor cell responses, and that a surrogate tissue can distinguish the metastatic potential of human breast cancer cell lines in an accessible site that avoids biopsy of a vital organ. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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Open AccessArticle

GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells

by Catalina M. Polanco, Viviana A. Cavieres, Abigail J. Galarza, Claudia Jara, Angie K. Torres, Jorge Cancino, Manuel Varas-Godoy, Patricia V. Burgos, Cheril Tapia-Rojas and Gonzalo A. Mardones

Cells 2024, 13(4), 316; https://doi.org/10.3390/cells13040316 - 8 Feb 2024

Cited by 3 | Viewed by 2310

Abstract

In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions [...] Read more.

In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions of these vesicles and potentially associated proteins remain unknown. GOLPH3, a PI(4)P-interacting GA protein, is elevated in various types of solid tumors, including breast cancer, yet its precise role is unclear. Interestingly, GOLPH3 levels influence mitochondrial mass by affecting cardiolipin synthesis, an exclusive mitochondrial lipid. However, the mechanism by which GOLPH3 influences mitochondria is not fully understood. Our live-cell imaging analysis showed GFP-GOLPH3 associating with PI(4)P vesicles colocalizing with YFP-DRP1 at mitochondrial fission sites. We tested the functional significance of these observations with GOLPH3 knockout in MDA-MB-231 cells of breast cancer, resulting in a fragmented mitochondrial network and reduced bioenergetic function, including decreased mitochondrial ATP production, mitochondrial membrane potential, and oxygen consumption. Our findings suggest a potential negative regulatory role for GOLPH3 in mitochondrial fission, impacting mitochondrial function and providing insights into GA–mitochondria communication. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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14 pages, 3240 KiB  

Open AccessArticle

Gestational Intermittent Hypoxia Enhances Mammary Stem Cells and Alters Tumor Phenotype in Adult Female Offspring

by Jaitri Joshi, Yue Xiong, Molly Kuhn, Abigail B. Radcliff, Tracy L. Baker, Jyoti J. Watters and Lisa M. Arendt

Cells 2024, 13(3), 249; https://doi.org/10.3390/cells13030249 - 29 Jan 2024

Viewed by 1770

Abstract

An adverse perinatal environment can increase long-term cancer risk, although the precise nature of associated perinatal triggers remain unknown. Sleep apnea is a common condition during pregnancy, characterized by recurrent cessations in breathing during sleep, and the potential consequences of sleep apnea during [...] Read more.

An adverse perinatal environment can increase long-term cancer risk, although the precise nature of associated perinatal triggers remain unknown. Sleep apnea is a common condition during pregnancy, characterized by recurrent cessations in breathing during sleep, and the potential consequences of sleep apnea during pregnancy as it relates to breast cancer risk in offspring have not been explored. To model sleep apnea, Sprague-Dawley dams were exposed during gestation to nightly intermittent hypoxia (GIH) or normoxia (GNx), and the mammary glands of female offspring were examined. GIH offspring demonstrated increased epithelial stem and progenitor cell populations, which are associated with diminished transforming growth factor beta (TGFβ) activity. Elevations in adipose tissue stem cells in the mammary gland were also identified in GIH offspring. In aging females, mammary tumors formed in GIH offspring. These tumors displayed a dramatic increase in stroma compared to tumors from GNx offspring, as well as distinct patterns of expression of stem cell-related pathways. Together, these results suggest that exposure to sleep apnea during pregnancy leads to lasting changes in the mammary glands of female offspring. Increased stem and progenitor cell populations as a result of GIH exposure could enhance long-term breast cancer risk, as well as alter the clinical behavior of resulting breast tumors. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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12 pages, 1267 KiB  

Open AccessArticle

The Risk Function of Breast and Ovarian Cancers in the Avrami–Dobrzyński Cellular Phase-Transition Model

by Anna Zawadzka, Beata Brzozowska, Anna Matyjanka, Michał Mikula, Joanna Reszczyńska, Adrianna Tartas and Krzysztof W. Fornalski

Int. J. Mol. Sci. 2024, 25(2), 1352; https://doi.org/10.3390/ijms25021352 - 22 Jan 2024

Cited by 2 | Viewed by 1906

Abstract

Specifying the role of genetic mutations in cancer development is crucial for effective screening or targeted treatments for people with hereditary cancer predispositions. Our goal here is to find the relationship between a number of cancerogenic mutations and the probability of cancer induction [...] Read more.

Specifying the role of genetic mutations in cancer development is crucial for effective screening or targeted treatments for people with hereditary cancer predispositions. Our goal here is to find the relationship between a number of cancerogenic mutations and the probability of cancer induction over the lifetime of cancer patients. We believe that the Avrami–Dobrzyński biophysical model can be used to describe this mechanism. Therefore, clinical data from breast and ovarian cancer patients were used to validate this model of cancer induction, which is based on a purely physical concept of the phase-transition process with an analogy to the neoplastic transformation. The obtained values of model parameters established using clinical data confirm the hypothesis that the carcinogenic process strongly follows fractal dynamics. We found that the model’s theoretical prediction and population clinical data slightly differed for patients with the age below 30 years old, and that might point to the existence of an ancillary protection mechanism against cancer development. Additionally, we reveal that the existing clinical data predict breast or ovarian cancers onset two years earlier for patients with BRCA1/2 mutations. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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18 pages, 2921 KiB  

Open AccessReview

Integrins and Actions of Androgen in Breast Cancer

by Chung-Che Tsai, Yu-Chen S. H. Yang, Yi-Fong Chen, Lin-Yi Huang, Yung-Ning Yang, Sheng-Yang Lee, Wen-Long Wang, Hsin-Lun Lee, Jacqueline Whang-Peng, Hung-Yun Lin and Kuan Wang

Cells 2023, 12(17), 2126; https://doi.org/10.3390/cells12172126 - 22 Aug 2023

Cited by 7 | Viewed by 2683

Abstract

Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells [...] Read more.

Androgen has been shown to regulate male physiological activities and cancer proliferation. It is used to antagonize estrogen-induced proliferative effects in breast cancer cells. However, evidence indicates that androgen can stimulate cancer cell growth in estrogen receptor (ER)-positive and ER-negative breast cancer cells via different types of receptors and different mechanisms. Androgen-induced cancer growth and metastasis link with different types of integrins. Integrin αvβ3 is predominantly expressed and activated in cancer cells and rapidly dividing endothelial cells. Programmed death-ligand 1 (PD-L1) also plays a vital role in cancer growth. The part of integrins in action with androgen in cancer cells is not fully mechanically understood. To clarify the interactions between androgen and integrin αvβ3, we carried out molecular modeling to explain the potential interactions of androgen with integrin αvβ3. The androgen-regulated mechanisms on PD-L1 and its effects were also addressed. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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14 pages, 1278 KiB  

Open AccessReview

Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches

by Sayra Dilmac and Bulent Ozpolat

Cancers 2023, 15(14), 3642; https://doi.org/10.3390/cancers15143642 - 16 Jul 2023

Cited by 23 | Viewed by 10058

Abstract

The recent success of Poly (ADP-ribose) polymerase (PARP) inhibitors has led to the approval of four different PARP inhibitors for the treatment of BRCA1/2-mutant breast and ovarian cancers. About 40–50% of BRCA1/2-mutated patients do not respond to PARP inhibitors due to a preexisting [...] Read more.

The recent success of Poly (ADP-ribose) polymerase (PARP) inhibitors has led to the approval of four different PARP inhibitors for the treatment of BRCA1/2-mutant breast and ovarian cancers. About 40–50% of BRCA1/2-mutated patients do not respond to PARP inhibitors due to a preexisting innate or intrinsic resistance; the majority of patients who initially respond to the therapy inevitably develop acquired resistance. However, subsets of patients experience a long-term response (>2 years) to treatment with PARP inhibitors. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that plays an important role in the recognition and repair of DNA damage. PARP inhibitors induce “synthetic lethality” in patients with tumors with a homologous-recombination-deficiency (HRD). Several molecular mechanisms have been identified as causing PARP-inhibitor-resistance. In this review, we focus on the molecular mechanisms underlying the PARP-inhibitor-resistance in BRCA-mutated breast cancer and summarize potential therapeutic strategies to overcome the resistance mechanisms. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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16 pages, 2957 KiB  

Open AccessArticle

A New Culture Model for Enhancing Estrogen Responsiveness in HR+ Breast Cancer Cells through Medium Replacement: Presumed Involvement of Autocrine Factors in Estrogen Resistance

by Seok-Hoon Jang, Se Hyun Paek, Jong-Kyu Kim, Je Kyung Seong and Woosung Lim

Int. J. Mol. Sci. 2023, 24(11), 9474; https://doi.org/10.3390/ijms24119474 - 30 May 2023

Cited by 2 | Viewed by 2591

Abstract

Hormone receptor-positive breast cancer (HR+ BC) cells depend on estrogen and its receptor, ER. Due to this dependence, endocrine therapy (ET) such as aromatase inhibitor (AI) treatment is now possible. However, ET resistance (ET-R) occurs frequently and is a priority in HR+ BC [...] Read more.

Hormone receptor-positive breast cancer (HR+ BC) cells depend on estrogen and its receptor, ER. Due to this dependence, endocrine therapy (ET) such as aromatase inhibitor (AI) treatment is now possible. However, ET resistance (ET-R) occurs frequently and is a priority in HR+ BC research. The effects of estrogen have typically been determined under a special culture condition, i.e., phenol red-free media supplemented with dextran-coated charcoal-stripped fetal bovine serum (CS-FBS). However, CS-FBS has some limitations, such as not being fully defined or ordinary. Therefore, we attempted to find new experimental conditions and related mechanisms to improve cellular estrogen responsiveness based on the standard culture medium supplemented with normal FBS and phenol red. The hypothesis of pleiotropic estrogen effects led to the discovery that T47D cells respond well to estrogen under low cell density and medium replacement. These conditions made ET less effective there. The fact that several BC cell culture supernatants reversed these findings implies that housekeeping autocrine factors regulate estrogen and ET responsiveness. Results reproduced in T47D subclone and MCF-7 cells highlight that these phenomena are general among HR+ BC cells. Our findings offer not only new insights into ET-R but also a new experimental model for future ET-R studies. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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20 pages, 2764 KiB  

Open AccessArticle

SRSF5 Regulates the Expression of BQ323636.1 to Modulate Tamoxifen Resistance in ER-Positive Breast Cancer

by Ho Tsoi, Nicholas Nok-Ching Fung, Ellen P. S. Man, Man-Hong Leung, Chan-Ping You, Wing-Lok Chan, Sum-Yin Chan and Ui-Soon Khoo

Cancers 2023, 15(8), 2271; https://doi.org/10.3390/cancers15082271 - 13 Apr 2023

Cited by 2 | Viewed by 2373

Abstract

About 70% of breast cancer patients are oestrogen receptor-positive (ER +ve). Adjuvant endocrine therapy using tamoxifen (TAM) is an effective approach for preventing local recurrence and metastasis. However, around half of the patients will eventually develop resistance. Overexpression of BQ323636.1 (BQ) is one [...] Read more.

About 70% of breast cancer patients are oestrogen receptor-positive (ER +ve). Adjuvant endocrine therapy using tamoxifen (TAM) is an effective approach for preventing local recurrence and metastasis. However, around half of the patients will eventually develop resistance. Overexpression of BQ323636.1 (BQ) is one of the mechanisms that confer TAM resistance. BQ is an alternative splice variant of NCOR2. The inclusion of exon 11 generates mRNA for NCOR2, while the exclusion of exon 11 produces mRNA for BQ. The expression of SRSF5 is low in TAM-resistant breast cancer cells. Modulation of SRSF5 can affect the alternative splicing of NCOR2 to produce BQ. In vitro and in vivo studies confirmed that the knockdown of SRSF5 enhanced BQ expression, and conferred TAM resistance; in contrast, SRSF5 overexpression reduced BQ expression and, thus, reversed TAM resistance. Clinical investigation using a tissue microarray confirmed the inverse correlation of SRSF5 and BQ. Low SRSF5 expression was associated with TAM resistance, local recurrence and metastasis. Survival analyses showed that low SRSF5 expression was associated with poorer prognosis. We showed that SRPK1 can interact with SRSF5 to phosphorylate it. Inhibition of SRPK1 by a small inhibitor, SRPKIN-1, suppressed the phosphorylation of SRSF5. This enhanced the proportion of SRSF5 interacting with exon 11 of NCOR2, reducing the production of BQ mRNA. As expected, SRPKIN-1 reduced TAM resistance. Our study confirms that SRSF5 is essential for BQ expression. Modulating the activity of SRSF5 in ER +ve breast cancer will be a potential approach to combating TAM resistance. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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18 pages, 7602 KiB  

Open AccessArticle

Hypoxia-Driven TGFβ Modulation of Side Population Cells in Breast Cancer: The Potential Role of ERα

by Paraskevi Mallini, Miaojuan Chen, Kamilla Mahkamova, Thomas W. J. Lennard, Yue Pan, Dan Wei, Katherine Stemke-Hale, John A. Kirby, Gendie E. Lash and Annette Meeson

Cancers 2023, 15(4), 1108; https://doi.org/10.3390/cancers15041108 - 9 Feb 2023

Cited by 4 | Viewed by 2694

Abstract

Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT [...] Read more.

Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl₂ exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl₂ treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl₂ exposure led to a significant increase. Single cell analysis revealed that CoCl₂ exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl₂ exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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26 pages, 8207 KiB  

Open AccessArticle

Transcriptome Analysis Reveals Vimentin-Induced Disruption of Cell–Cell Associations Augments Breast Cancer Cell Migration

by Saima Usman, Ahmad Jamal, Antesar Bushaala, Naushin H. Waseem, Hebah Al-Dehlawi, William Andrew Yeudall, Muy-Teck Teh, Hemanth Tummala and Ahmad Waseem

Cells 2022, 11(24), 4035; https://doi.org/10.3390/cells11244035 - 13 Dec 2022

Cited by 7 | Viewed by 3347

Abstract

In advanced metastatic cancers with reduced patient survival and poor prognosis, expression of vimentin, a type III intermediate filament protein is frequently observed. Vimentin appears to suppress epithelial characteristics and augments cell migration but the molecular basis for these changes is not well [...] Read more.

In advanced metastatic cancers with reduced patient survival and poor prognosis, expression of vimentin, a type III intermediate filament protein is frequently observed. Vimentin appears to suppress epithelial characteristics and augments cell migration but the molecular basis for these changes is not well understood. Here, we have ectopically expressed vimentin in MCF-7 and investigated its genomic and functional implications. Vimentin changed the cell shape by decreasing major axis, major axis angle and increased cell migration, without affecting proliferation. Vimentin downregulated major keratin genes KRT8, KRT18 and KRT19. Transcriptome-coupled GO and KEGG analyses revealed that vimentin-affected genes were linked to either cell–cell/cell-ECM or cell cycle/proliferation specific pathways. Using shRNA mediated knockdown of vimentin in two cell types; MCF-7FV (ectopically expressing) and MDA-MB-231 (endogenously expressing), we identified a vimentin-specific signature consisting of 13 protein encoding genes (CDH5, AXL, PTPRM, TGFBI, CDH10, NES, E2F1, FOXM1, CDC45, FSD1, BCL2, KIF26A and WISP2) and two long non-coding RNAs, LINC00052 and C15ORF9-AS1. CDH5, an endothelial cadherin, which mediates cell–cell junctions, was the most downregulated protein encoding gene. Interestingly, downregulation of CDH5 by shRNA significantly increased cell migration confirming our RNA-Seq data. Furthermore, presence of vimentin altered the lamin expression in MCF-7. Collectively, we demonstrate, for the first time, that vimentin in breast cancer cells could change nuclear architecture by affecting lamin expression, which downregulates genes maintaining cell–cell junctions resulting in increased cell migration. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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18 pages, 5110 KiB  

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Osteoprotegerin (OPG) Upregulation Activates Breast Stromal Fibroblasts and Enhances Their Pro-Carcinogenic Effects through the STAT3/IL-6 Signaling

by Huda K. Al-Nasrallah, Mysoon M. Al-Ansari and Abdelilah Aboussekhra

Cells 2022, 11(21), 3369; https://doi.org/10.3390/cells11213369 - 25 Oct 2022

Cited by 2 | Viewed by 2287

Abstract

Breast carcinomas are composed of cancer cells surrounded by various types of non-cancer cells such as fibroblasts. While active cancer-associated fibroblasts (CAFs) support tumor initiation and progression, quiescent breast stromal fibroblasts (BSFs) inhibit these effects through various cytokines such as osteoprotegerin (OPG). We [...] Read more.

Breast carcinomas are composed of cancer cells surrounded by various types of non-cancer cells such as fibroblasts. While active cancer-associated fibroblasts (CAFs) support tumor initiation and progression, quiescent breast stromal fibroblasts (BSFs) inhibit these effects through various cytokines such as osteoprotegerin (OPG). We showed here that OPG is upregulated in CAFs as compared to their adjacent normal tumor counterpart fibroblasts. Interestingly, breast cancer cells can upregulate OPG in BSFs in an IL-6-dependent manner through the IL-6/STAT3 pathway. When upregulated by ectopic expression, OPG activated BSFs through the NF-κB/STAT3/AUF1 signaling pathway and promoted their paracrine pro-carcinogenic effects in an IL-6-dependent manner. In addition, this increase in the OPG level enhanced the potential of BSFs to promote the growth of humanized orthotopic tumors in mice. However, specific OPG knock-down suppressed active CAFs and their paracrine pro-carcinogenic effects. Similar effects were observed when CAF cells were exposed to the pure recombinant OPG (rOPG) protein. Together, these findings show the importance of OPG in the activation of stromal fibroblasts and the possible use of rOPG or inhibitors of the endogenous protein to target CAFs as precision cancer therapeutics. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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13 pages, 3354 KiB  

Open AccessArticle

CUEDC2 Drives β-Catenin Nuclear Translocation and Promotes Triple-Negative Breast Cancer Tumorigenesis

by Shuyan Han, Huifeng Hao, Haibo Han, Dong Xue, Yanna Jiao, Yuntao Xie, Ye Xu, Longtao Huangfu, Jialei Fu, Shan Wang, Hong Sun, Pingping Li and Qun Zhou

Cells 2022, 11(19), 3067; https://doi.org/10.3390/cells11193067 - 29 Sep 2022

Cited by 5 | Viewed by 2713

Abstract

Hyperactivation of Wnt signaling is crucial in tumor formation. Fully elucidating the molecular details of how the cancer-specific Wnt signaling pathway is activated or contributes to tumorigenesis will help in determining future treatment strategies. Here, we aimed to explore the contribution of CUEDC2, [...] Read more.

Hyperactivation of Wnt signaling is crucial in tumor formation. Fully elucidating the molecular details of how the cancer-specific Wnt signaling pathway is activated or contributes to tumorigenesis will help in determining future treatment strategies. Here, we aimed to explore the contribution of CUEDC2, a novel CUE-domain-containing protein, to the activation of Wnt signaling and the tumorigenesis of triple-negative breast cancer (TNBC) and to determine the underlying mechanisms. TNBC patient samples and disease-free survival (DFS) data were used to determine the association between CUEDC2 and TNBC progression. The effects of CUEDC2 on TNBC were examined in TNBC cells in vitro and in subcutaneous xenograft tumors in vivo. Gene knockdown, immunoprecipitation plus liquid chromatography–tandem mass spectrometry, pull-down, co-immunoprecipitation, localized surface plasmon resonance, and nuclear translocation analysis were used to uncover the mechanisms of CUEDC2 in regulating Wnt signaling and TNBC development. CUEDC2 is sufficient to maintain the hyperactivation of Wnt signaling required for TNBC tumorigenesis. The contribution of CUEDC2 plays a major role in determining the outcome of oncogenic Wnt signaling both in vitro and in vivo. Mechanistically, the CUE domain in CUEDC2 directly bound to the ARM (7–9) domain in β-catenin, promoted β-catenin nuclear translocation and enhanced the expression of β-catenin targeted genes. More importantly, an 11-amino-acid competitive peptide targeting the CUE domain in CUEDC2 blocked the interactions of CUEDC2 and β-catenin and abrogated the malignant phenotype of TNBC cells in vitro and in vivo. We observed that TNBC patients who exhibited higher levels of CUEDC2 showed marked hyperactivation of the Wnt signaling pathway and poor clinical outcomes, highlighting the clinical relevance of our findings. CUEDC2 promotes TNBC tumor growth by enhancing Wnt signaling through directly binding to β-catenin and accelerating its nuclear translocation. Targeting the interactions of CUEDC2 and β-catenin may be a valuable strategy for combating TNBC. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Cancers: Breast Cancer)

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