Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

AbstractTriple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases.

Download Full-text

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

10.1101/2020.08.04.235697 ◽

2020 ◽

Author(s):

Samantha A Hutchinson ◽

Alex Websdale ◽

Giorgia Cioccoloni ◽

Hanne Røberg-Larsen ◽

Priscilia Lianto ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Chemotherapy Resistance ◽

Resistance Mechanism ◽

P Glycoprotein ◽

Tumor Tissues ◽

X Receptors ◽

Necessary And Sufficient

Download Full-text

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-015-3430-3 ◽

2015 ◽

Vol 151 (3) ◽

pp. 541-553 ◽

Cited By ~ 25

Author(s):

Shaham Beg ◽

Abdul K. Siraj ◽

Sarita Prabhakaran ◽

Zeenath Jehan ◽

Dahish Ajarim ◽

...

Keyword(s):

Breast Cancer ◽

Aggressive Behavior ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Middle Eastern ◽

Pten Expression

Download Full-text

Low Expression of Circulating MicroRNA-34c is Associated with Poor Prognosis in Triple-Negative Breast Cancer

Yonsei Medical Journal ◽

10.3349/ymj.2017.58.4.697 ◽

2017 ◽

Vol 58 (4) ◽

pp. 697 ◽

Cited By ~ 24

Author(s):

Zhihao Zeng ◽

Xiaowu Chen ◽

Dajian Zhu ◽

Zhongran Luo ◽

Min Yang

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Circulating Microrna ◽

Low Expression

Download Full-text

High expression of UBD correlates with epirubicin resistance and indicates poor prognosis in triple-negative breast cancer

OncoTargets and Therapy ◽

10.2147/ott.s81214 ◽

2015 ◽

pp. 1643 ◽

Cited By ~ 1

Author(s):

Xiaodong Xie ◽

TAO HAN ◽

Yaling Han ◽

Wanqing Xie ◽

Ranran Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

High Expression

Download Full-text

Biological and clinical significance of flap endonuclease‑1 in triple‑negative breast cancer: Support of metastasis and a poor prognosis

Oncology Reports ◽

10.3892/or.2020.7812 ◽

2020 ◽

Vol 44 (6) ◽

pp. 2443-2454

Author(s):

Lu Xu ◽

Jing‑Lei Qu ◽

Na Song ◽

Ling‑Yun Zhang ◽

Xue Zeng ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Significance ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Flap Endonuclease 1 ◽

Cancer Support

Download Full-text

Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Medicina ◽

10.3390/medicina57080837 ◽

2021 ◽

Vol 57 (8) ◽

pp. 837

Author(s):

So-Woon Kim ◽

Jinah Chu ◽

Sung-Im Do ◽

Kiyong Na

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

Histological Grade ◽

Growth Factor Receptor ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B ◽

Epidermal Growth

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

Download Full-text

Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

Nature Communications ◽

10.1038/s41467-021-24878-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Katsutoshi Sato ◽

Amol A. Padgaonkar ◽

Stacey J. Baker ◽

Stephen C. Cosenza ◽

Olga Rechkoblit ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Kinase Inhibitor ◽

Chemotherapy Resistance ◽

Metastatic Progression ◽

Resistant Disease ◽

Risk Patients ◽

Additional Support

AbstractTriple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.

Download Full-text