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Critical Targets and Therapeutic Strategies of Breast Cancer

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Dear Colleagues,

Breast cancer is the most common type of cancer in women and remains a significant scientific and clinical in the realm of public health. Recent technological advances in molecular biology and biochemical approaches have allowed the dissection of tumor heterogeneity and complexity, highlighting the specific pathophysiology of different types of breast cancer.
However, the challenges still to be overcome before we reach the goal of an effective personalized medicine are the lack of prognostic and predictive biomarkers for all breast cancer subtypes and the emergence of therapeutic resistance mechanisms. Indeed, the development of chemo- or radioresistance, and more recently also resistance to immunotherapy, can be attributed to tumor microenvironments components, epigenetic changes, and alterations of the cell signaling pathways/genes associated with the activity of cancer stem cells (CSCs). Thus, further studies that contribute to providing a more detailed picture of the cytological differences of breast cancer cells of different subtypes and during the various phases of tumor progression could also have a strong impact on the clinical setting.
The main scope of this Special Issue addresses a thorough update of recent biological observations including, but not limited to, the following areas:

Markers characterizing the various breast tumor subtypes;
Cellular responses in terms of morphological and functional changes during the breast cancer progression;
Immune cell crosstalk with tumor cells in the breast tumor environment;
Epigenetic changes during malignant transformation and progression;
Impact of lifestyle changes on breast cancer cells features;
Molecular drivers behind breast cancer subtypes and tumor heterogeneity;
Biomarkers for chemosensitivity and radiosensitivity.

Dr. Francesca Bianchi
Dr. Alessandra Cataldo
Guest Editors

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Keywords

biomarkers
microenvironment
subtypes
dormancy
therapy
resistance

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21 pages, 6042 KiB

Open AccessArticle

Chronic High-Salt Diet Activates Tumor-Initiating Stem Cells Leading to Breast Cancer Proliferation

by Lisa Tucker, Umer Ali, Roy Zent, Deborah A. Lannigan, Jeffrey C. Rathmell and Venkataswarup Tiriveedhi

Cells 2024, 13(11), 912; https://doi.org/10.3390/cells13110912 - 25 May 2024

Viewed by 1140

Abstract

Several chronic inflammatory diseases have been linked to high-salt (HS) diets. Chronic inflammation is an established causative hallmark of cancer. However, a direct role of HS diets in tumorigenesis is yet to be defined. Previous orthotopic murine breast tumor studies have shown that short-term HS diets caused inhibition of tumor growth through the activation of cytotoxic adaptive immune responses. However, there have been experimental challenges in developing a viable chronic HS-diet-based murine tumor model. To address this, we have developed a novel chronic HS diet tumor model through the sequential passaging of tumor cells in mice under HS dietary conditions. Two orthotopic murine triple-negative breast cancer models, 4T1 tumor cells injected into BALB/c mice and Py230 tumor cells injected into C57Bl/6 mice, were utilized in our study. For the HS diet cohort, prior to orthotopic injection with tumor cells, the mice were kept on a 4% NaCl diet for 2 weeks. For the regular salt (RS) diet cohort, the mice were kept on a 1% NaCl diet. Following syngeneic cancer cell injection, tumors were allowed to grow for 28 days, following which they were collected to isolate immune cell-depleted cancer cells (passage 1, P1). The tumor cells from P1 were reinjected into the next set of non-tumor-bearing mice. This procedure was repeated for three cycles (P2–P4). In P1, compared to the RS diet cohort, we observed reduced tumor kinetics in both murine tumor models on the HS diet. In contrast, by P4, there was significantly higher tumor progression in the HS diet cohort over the RS diet cohort. Flow cytometry analysis demonstrated an 8-fold increase in tumor-initiating stem cells (TISCs) from P1 to P4 of the HS diet cohort, while there were no significant change in TISC frequency with sequential passaging in the RS diet cohort. Molecular studies showed enhanced expression of TGFβR2 and CD80 on TISCs isolated from the P4 HS diet cohort. In vitro studies demonstrated that TGFβ stimulation of these TISCs increased the cellular expression of CD80 molecules. Further, the chronic HS diet selectively induced the glycolytic metabolic phenotype over the mitochondrial oxidative phosphorylation phenotype in TISCs, which is needed for the production of metabolites during tumor cell differentiation and proliferation. The infiltrating CD8 and CD4 T-lymphocytes in P4 tumors demonstrated increased expression of the immune checkpoint inhibitor (ICI) CTLA4, a known binding partner of CD80, to cause immune exhaustion and pro-tumorigenic effects. Interestingly, anti-TGFβ monoclonal antibodies (mAbs) played a synergistic role in further enhancing the anti-tumor effect of anti-CTLA4 mAb. In summary, our findings demonstrated that chronic HS diet increased the frequency of TISCs in tumors leading to blunting of cytotoxic adaptive immune responses causing tumor proliferation. Furthermore, a combination of anti-TGFβ with current ICI-based immunotherapies could exert more favorable anti-cancer clinical outcomes. Full article

(This article belongs to the Special Issue Critical Targets and Therapeutic Strategies of Breast Cancer)

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