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Cancers
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Signaling Pathways in Breast Cancer
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Signaling Pathways in Breast Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 10540

Special Issue Editor

Prof. Dr. Sharad S. Singhal

E-Mail Website
Guest Editor
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010-3000, USA
Interests: carcinogenesis and metastases; chemoprevention; drug resistance; radiation resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Breast cancer is a major cause of death among women in the Western world, who have a significant lifetime risk of developing the disease. Nearly 40,000 women succumb to breast cancer every year in the United States alone. Breast cancer is a heterogeneous disease broadly classified into different subtypes and each with a distinct gene expression signature, including luminal-type, basal-like, human epidermal growth factor receptor 2-positive, and normal-like. Metastasis to multiple organs is the primary cause of mortality in breast cancer patients. HER2 is an important determinant of poor prognosis in breast cancer patients, and HER2-positive tumors are mostly resistant to therapy and have high metastatic potential. In addition, the intention of this Special Issue is to provide a succinct overview about the availability and relevance of the major categories of mouse models for breast cancer. This Special Issue will concentrate on the latest achievements in developing genetically engineered mice (GEM) with conditional knockout alleles or models that allow the inducible expression of oncogenes in mammary epithelial cells.

Thus, the aim of this Special Issue is to attract original research articles, clinical studies, and review articles describing the current findings on therapeutically promising natural products or small molecule inhibitors for future clinical use. We invite authors to submit articles that explore aspects of therapeutic potential of natural products and/or small molecule inhibitor(s) in the treatment and suppression of breast cancer progression and metastasis.

Prof. Dr. Sharad S. Singhal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • angiogenesis
  • apoptosis
  • breast cancer metastasis
  • breast cancer stem cells
  • cancer invasion
  • chemoprevention
  • epithelial-to-mesenchymal transition
  • ERα/ERBB2/HER2/NFκB/Notch3/TGFβ signaling
  • mammary carcinogenesis
  • mitochondrial dynamics
  • tumor microenvironment

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Published Papers (4 papers)

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Research

17 pages, 2911 KiB  
Article
P2Y2R-Mediated PAK1 Activation Is Involved in ESM-1 Overexpression in RT-R-MDA-MB-231 through FoxO1 Regulation
by Hana Jin and Hye Jung Kim
Cancers 2022, 14(17), 4124; https://doi.org/10.3390/cancers14174124 - 26 Aug 2022
Cited by 1 | Viewed by 1611
Abstract
ESM-1, overexpressed in several cancer types, is a potential cancer diagnostic and prognostic indicator. In our previous study, we determined that RT-R-TNBC cells were more aggressive than TNBC cells, and this difference was associated with ESM-1 overexpression. However, the mechanism explaining upregulated ESM-1 [...] Read more.
ESM-1, overexpressed in several cancer types, is a potential cancer diagnostic and prognostic indicator. In our previous study, we determined that RT-R-TNBC cells were more aggressive than TNBC cells, and this difference was associated with ESM-1 overexpression. However, the mechanism explaining upregulated ESM-1 expression in RT-R-TNBC cells compared to TNBC cells was unclear. Therefore, we aimed to identify the mechanism by which ESM-1 is overexpressed in RT-R-MDA-MB-231 cells. RT-R-MDA-MB-231 cells were treated with various ESM-1 transcription factor inhibitors, and only the FoxO1 inhibitor downregulated ESM-1 expression. FoxO1 nuclear localization was modulated by JNK and p38 MAPKs, which were differentially regulated by PKC, PDK1 and PAK1. PAK1 profoundly modulated JNK and p38 MAPKs, whereas PKC and PDK1 affected only p38 MAPK. P2Y2R activated by ATP, which is highly released from RT-R-BC cells, was involved in PAK1 activation, subsequent JNK and p38 MAPK activation, FoxO1 induction, and ESM-1 expression in RT-R-MDA-MB-231 cells. These findings suggest for the first time that ESM-1 was overexpressed in RT-R-MDA-MB-231 cells and regulated through the P2Y2R-PAK1-FoxO1 signaling pathway. Full article
(This article belongs to the Special Issue Signaling Pathways in Breast Cancer)
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15 pages, 7386 KiB  
Article
The Role of Runx2 in Microtubule Acetylation in Bone Metastatic Breast Cancer Cells
by Ahmad Othman, Marcus Winogradzki, Shreya Patel, Waddell Holmes, Alan Blank and Jitesh Pratap
Cancers 2022, 14(14), 3436; https://doi.org/10.3390/cancers14143436 - 15 Jul 2022
Cited by 5 | Viewed by 2308
Abstract
Bone metastasis of breast cancer results in severe bone loss, fractures, and death. Crosstalk between breast cancer cells and bone resident cells promotes osteoclast activity and the release of growth factors from the bone matrix resulting in aggressive tumor growth and bone loss. [...] Read more.
Bone metastasis of breast cancer results in severe bone loss, fractures, and death. Crosstalk between breast cancer cells and bone resident cells promotes osteoclast activity and the release of growth factors from the bone matrix resulting in aggressive tumor growth and bone loss. We and others have shown that Runt-related transcription factor-2 (Runx2) promotes metastatic tumor growth-associated bone loss. Breast cancer cells also induce autophagy to survive metabolic stress at the metastatic site. Recently, we reported a Runx2-dependent increase in autophagy. In this study, to examine the underlying mechanisms of metastasis and tumor resistance to stress, we used a bone metastatic isogenic variant of breast cancer MDA-MB-231 cells isolated from a xenograft tumor mouse model of metastasis. Our results with immunofluorescence and biochemical approaches revealed that Runx2 promotes microtubule (MT) stability to facilitate autophagy. Stable MTs are critical for autophagosome trafficking and display increased acetylation at Lysine 40 of α-tubulin. Runx2 silencing decreases acetylated α-tubulin levels. The expression levels of HDAC6 and αTAT1, which serve to regulate the acetylation of α-tubulin, were not altered with Runx2 silencing. We found that HDAC6 interaction with α-tubulin is inhibited by Runt-related factor-2 (Runx2). We show that the expression of wild-type Runx2 can restore the acetylated polymer of MTs in Runx2 knockdown cells, while the C-terminal deletion mutant fails to rescue the polymer of MTs. Importantly, cellular stress, such as glucose starvation also increases the acetylation of α-tubulin. We found that the loss of Runx2 increases the sensitivity of breast cancer cells to MT-targeting agents. Overall, our results indicate a novel regulatory mechanism of microtubule acetylation and suggest that Runx2 and acetylated microtubules may serve as therapeutic targets for bone metastatic tumors. Full article
(This article belongs to the Special Issue Signaling Pathways in Breast Cancer)
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19 pages, 4307 KiB  
Article
RON (MST1R) and HGFL (MST1) Co-Overexpression Supports Breast Tumorigenesis through Autocrine and Paracrine Cellular Crosstalk
by Brian G. Hunt, Angelle Jones, Carissa Lester, James C. Davis, Nancy M. Benight and Susan E. Waltz
Cancers 2022, 14(10), 2493; https://doi.org/10.3390/cancers14102493 - 19 May 2022
Cited by 4 | Viewed by 2828
Abstract
Background: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON (MST1R) and HGFL (MST1) genes are located on human chromosome 3 [...] Read more.
Background: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON (MST1R) and HGFL (MST1) genes are located on human chromosome 3 and mouse chromosome 9 respectively and are found near each other in both species. Based on co-expression patterns, we posited that RON and HGFL are co-regulated and that coordinate upregulation drives aggressive tumorigenesis. Methods: Mouse models were used to establish the functional significance of RON and HGFL co-overexpression on the activation of tumor cells and tumor-associated macrophages in breast cancer. TCGA and METABRIC gene expression and alteration data were used to query the relationships between MST1R and MST1 in breast cancer. Results: In tumor models, physiologic sources of HGFL modestly improve Arginase-1+ (M2) macrophage recruitment to the tumor proper. Tumor-cell produced HGFL functions in autocrine to sustain tumor cell RON activation and MAPK-dependent secretion of chemotactic factors and in paracrine to activate RON on macrophages and to promote breast cancer stem cell self-renewal. In silico analyses support that RON and HGFL are co-expressed across virtually all cancer types including breast cancer and that common genomic alterations do not appear to be drivers of RON/HGFL co-overexpression. Conclusions: Co-overexpression of RON and HGFL in breast cancer cells (augmented by physiologic sources of HGFL) promotes tumorigenesis through autocrine-mediated RON activation/RON-dependent secretome changes and paracrine activation of macrophage RON to promote breast cancer stem cell self-renewal. Full article
(This article belongs to the Special Issue Signaling Pathways in Breast Cancer)
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15 pages, 3497 KiB  
Article
Global Genomic and Proteomic Analysis Identified Critical Pathways Modulated by Proto-Oncogene PELP1 in TNBC
by Zexuan Liu, Kristin A. Altwegg, Junhao Liu, Susan T. Weintraub, Yidong Chen, Zhao Lai, Gangadhara R. Sareddy, Suryavathi Viswanadhapalli and Ratna K. Vadlamudi
Cancers 2022, 14(4), 930; https://doi.org/10.3390/cancers14040930 - 13 Feb 2022
Cited by 6 | Viewed by 3141
Abstract
The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and [...] Read more.
The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and alterations in the proteome were examined using global data-independent acquisition mass spectrometry (DIA-MS). Further mechanistic studies utilized shRNA knockdown, Western blotting, and RNA-seq approaches. TCGA data sets were utilized for determining the status of PELP1 in TNBC patient tumors and for examining its correlation with ribosomal proteins. Global DIA-MS studies revealed that 127 proteins are upregulated while 220 proteins are downregulated upon PELP1-KO. Bioinformatic analyses suggested that the oncogenic activities of PELP1 involve regulation of expression of ribosomal proteins and ribosomal complexes. RNA-seq studies further suggested PELP1 modulates the functions of transcription factor c-Myc in TNBC. TCGA data confirmed PELP1 has high expression in TNBC patient tumors, and this high expression pattern correlates with c-Myc, a regulator of ribosomal proteins. Collectively, our global approach studies suggest that PELP1 contributes to TNBC progression by modulation of cell cycle, apoptosis, and ribosome biogenesis pathways. Full article
(This article belongs to the Special Issue Signaling Pathways in Breast Cancer)
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