bims-merabr 2024-12-01 papers

Int J Mol Sci. 2024 Nov 11. pii: 12102. [Epub ahead of print]25(22):

Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer.

HER2 overexpression occurs in 20-30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software (version 1.0) to identify synergistic doses (CI < 1). The synergistic concentrations' impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey's post hoc test (p < 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.

Keywords: breast cancer; hedgehog; stemness

DOI: https://doi.org/10.3390/ijms252212102

J Cancer Res Clin Oncol. 2024 Nov 26. 150(12): 512

TTK promotes HER2 + breast cancer cell migration, apoptosis, and resistance to targeted therapy by modulating the Akt/mTOR axis.

Shaolin Zhang, Hua Ding, Yongfen Deng, Yu Ren, Fulin Zhou, Qian Zhang, Shu Liu.

BACKGROUND: HER2 + breast cancer is a malignant neoplasm with a high degree of aggressiveness and therapeutic challenge. In recent years, studies have indicated a strong correlation between TTK and various tumors, though its role in HER2 + BRCA remains unclear.
OBJECTIVES: Studying the biological function of the TTK gene in HER2 + BRCA and its resistance to targeted therapy it provides new ideas for targeted drug research.
METHODS: TTK was knocked down by small interfering RNA transfection, and its biological function in HER2 + BRCA cells was verified, and its mechanism of action was verified by RT-PCR and Western blot.
RESULTS: The study demonstrated that TTK promoted cell proliferation and migration by activating the Akt/mTOR pathway in HER2 + breast cancer and enhanced the drug sensitivity of BRCA cell lines SKBR3 and BT474 to pyrotinib, in addition, knockdown of TTK induced apoptosis and arrested cells in G1 phase.
CONCLUSION: Which implies that TTK is an oncogene in HER2 + BRCA and is a valuable research target.

Keywords: Apoptosis; Drug resistance; HER2 + breast cancer; Igration; Target

DOI: https://doi.org/10.1007/s00432-024-06021-9

Front Biosci (Landmark Ed). 2024 Oct 30. 29(11): 371

NUF2 Promotes Breast Cancer Metastasis via Activating Wnt/β-Catenin Pathways.

Nijiati AiErken, Xidi Wang, Jiamei Wang, Weisen Ma, Lingfei Cui, Mingxia Zhang, Weifeng Ma, Dongwei Liu.

BACKGROUND: Breast cancer is the most common malignancy and the leading cause of cancer death among women. NDC80 kinetochore complex component (NUF2) is demonstrated to implicate the progression of human cancer. But the role of NUF2 in breast cancer progression is unclear. Here, we aimed to study the role and regulatory mechanisms of NUF2 in breast cancer metastasis.
METHODS: Immunohistochemistry was used to determine UNF2 expression in clinical samples. Transwell assas were used to determine the role of NUF2 in breast cancer migration and invasion. Animal model in vivo was used to determine the rold of NUF2 in breast cancer metastasis.
RESULTS: NUF2 was upregulated significantly in breast cancer tissues and cells. Worse prognosis was noted in patients with high NUF2 levels compared with that in patients with low NUF2 levels. NUF2 overexpression markedly enhanced, while NUF2 knockdown inhibited, breast cancer cell invasion and migration. Mechanistically, NUF2 was observed to upregulate Wnt/β-catenin signaling pathway activity. The promoting effect of NUF2 on cell migration and invasion were blocked by inhibition of the Wnt/β-catenin pathway.
CONCLUSIONS: We revealed that NUF2 promotes breast cancer progression via activating Wnt/β-catenin signaling, suggesting that NUF2 might be a new potential target for breast cancer treatment.

Keywords: NUF2; Wnt/β-catenin; breast cancer; invasion; migration

DOI: https://doi.org/10.31083/j.fbl2911371

Curr Issues Mol Biol. 2024 Oct 30. 46(11): 12214-12229

Targeting PGK1: A New Frontier in Breast Cancer Therapy Under Hypoxic Conditions.

Jiayong Cui, Shengjun Chai, Rui Liu, Guoshuang Shen.

Breast cancer represents one of the most prevalent malignant neoplasms affecting women, and its pathogenesis has garnered significant scholarly interest. Research indicates that the progression of breast cancer is intricately regulated by glucose metabolism. Under hypoxic conditions within the tumor microenvironment, breast cancer cells generate ATP and essential biosynthetic precursors for growth via the glycolytic pathway. Notably, phosphoglycerate kinase 1 (PGK1) is intimately associated with the regulation of hypoxia-inducible factors in breast cancer and plays a crucial role in modulating glycolytic processes. Further investigation into the role of PGK1 in breast cancer pathogenesis is anticipated to identify novel therapeutic targets and strategies. This review consolidates current research on the regulation of glucose metabolism and the function of PGK1 in breast cancer within hypoxic conditions. It aims to offer a significant theoretical foundation for elucidating the mechanisms underlying breast cancer progression and metastasis, thereby facilitating the development of innovative treatment approaches.

Keywords: HIF-1α; PGK1; breast cancer; glycolysis; hypoxia

DOI: https://doi.org/10.3390/cimb46110725

Adv Exp Med Biol. 2024 ;1465 37-53

The Epigenetic Landscape of Breast Cancer, Metabolism, and Obesity.

Ashley Townsel, Maya Jaffe, Yifei Wu, Curtis J Henry, Karmella A Haynes.

Obesity is a risk factor for developing breast cancer, and significantly increases mortality rates in patients diagnosed with this disease. Drivers of this unfortunate relationships are multifactorial, with obesity-induced changes in the epigenetic state of breast cancer cells being identified as a critical mechanism that impact survival, metastasis, and therapeutic responses. Recent studies have investigated the epigenetic landscape of breast cancer to elucidate the molecular interplay between the breast tissue epigenome and its cellular microenvironment. This chapter highlights studies that demonstrates the impact of obesity on the epigenome and metabolome of breast cancer cells. Furthermore, we discuss how obesity impacts the efficacy of chemotherapy and epigenetic targeting drugs, including the emergence of drug-resistance clonal populations. Delineating the relationships between the obesity and epigenetic changes in breast cancer cells will help identify therapeutic strategies which could improve survival outcomes in the rapidly growing number of patients with obesity and cancer.

Keywords: Cancer metabolic pathways; Intratumoral heterogeneity; Obesity; S-Adenosyl methionine; T-cell-mediated Immunity

DOI: https://doi.org/10.1007/978-3-031-66686-5_3

Cancers (Basel). 2024 Nov 15. pii: 3840. [Epub ahead of print]16(22):

Carcinoma-Associated Fibroblasts Accelerate Growth and Invasiveness of Breast Cancer Cells in 3D Long-Term Breast Cancer Models.

Kingsley O Osuala, Joshua Heyza, Zhiguo Zhao, Yong Xu, Kamiar Moin, Kyungmin Ji, Raymond R Mattingly.

Background/Objectives: Carcinoma-associated fibroblasts (CAFs), a prominent cell type in the tumor microenvironment (TME), significantly contributes to cancer progression through interactions with cancer cells and other TME components. Consequently, targeting signaling pathways driven by CAFs has potential to yield new therapeutic approaches to inhibit cancer progression. However, the mechanisms underlying their long-term interactions with cancer cells in vivo remains poorly understood. Methods: To address this, we developed a three-dimensional (3D) parallel coculture model of human triple-negative breast cancer (TNBC) cells and CAFs using our innovative TAME devices. This model allowed for the analysis of TNBC paracrine interactions via their secretome over extended culture periods (at least 70 days). Results: Using TNBC cell lines (MDA-MB-231, MCF10.DCIS, and HCC70), we found that TNBC spheroids in 3D parallel cocultures with CAFs exhibited more pronounced invasive finger-like outgrowths than those in cocultures of TNBC cells and normal fibroblasts (NFs) over a period of 50-70 days. We also established that the CAF-derived secretome affects TNBC migration towards the CAF secretome region. Additionally, we observed a preferential migration of CAFs, but not NFs, toward TNBC spheroids. Conclusions: Overall, our results suggest that paracrine interactions between TNBC cells and CAFs enhance TNBC invasive phenotypes and promote reciprocal migration.

Keywords: 3D parallel cocultures; carcinoma-associated fibroblasts (CAFs); microfluidic devices; triple-negative breast cancer (TNBC)

DOI: https://doi.org/10.3390/cancers16223840