HUNK phosphorylates EGFR to regulate breast cancer metastasis

Abstract Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.

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Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

Cancers ◽

10.3390/cancers12071827 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1827 ◽

Cited By ~ 2

Author(s):

Grace L. Wong ◽

Sara Abu Jalboush ◽

Hui-Wen Lo

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Tumor Microenvironment ◽

Cancer Metastasis ◽

Current Knowledge ◽

Metastatic Breast ◽

Tumor Stroma ◽

Breast Cancer Metastasis ◽

Exosomal Mirnas ◽

Made In

Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs.

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Factors associated with mortality after breast cancer metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.174 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 174-174

Author(s):

S. Y. Jung ◽

M. Q. Rosenzweig ◽

S. M. Sereika ◽

F. Linkov ◽

A. Brufsky ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Cancer Metastasis ◽

Cox Regression ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Her2 Status ◽

Breast Cancer Patients

174 Background: It is generally accepted that patients with breast cancer metastases have poor survival. Metastatic breast cancer patients can be considered a heterogeneous population with a varied clinical course, which underscores the need for accurate prediction of survival based on prognostic factors. The purpose of the present study was to identify factors related to survival in breast cancer patients after diagnosis with metastatic disease. Methods: A total of 557 patients with breast cancer metastasis diagnosis seen at one large urban practice have been followed up between January 1, 1999 and June 30, 2008. Demographic, tumor characteristics, clinical factors as predictors of survival were analyzed using Cox regression model. Results: The median survival length was 40 months (range 1-114 months) with 269 (48.3%) alive and 288 (51.7%) dead. This study demonstrated that hypertension, estrogen receptor (ER) and/or progesterone receptor (PR) status, human epidermal growth factor receptor-2 (HER2) status, number of metastatic sites, and body mass index (BMI) at diagnosis with metastatic breast cancer were the most relevant prognostic factors for survival after metastasis. Conclusions: Findings of this study may form a foundation for the corpus of knowledge explaining the outcome differences in treatment of patients with metastatic breast cancer, potentially helping to create tailored counseling and personalized treatment approaches for this vulnerable group. [Table: see text]

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Metastatic Breast Cancer, Organotropism and Therapeutics: A Review

Current Cancer Drug Targets ◽

10.2174/1568009621666210806094410 ◽

2021 ◽

Vol 21 ◽

Author(s):

Ajaz Ahmad Waza ◽

Najeebul Tarfeen ◽

Sabhiya Majid ◽

Yasmeena Hassan ◽

Rashid Mir ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Breast Cancer Metastases ◽

Cancer Metastases ◽

Main Culprit

: The final stage of breast cancer involves spreading breast cancer cells to the vital organs like the brain, liver lungs and bones in the process called metastasis. Once the target organ is overtaken by the metastatic breast cancer cells, its usual function is compromised causing organ dysfunction and death. Despite the significant research on breast cancer metastasis, it’s still the main culprit of breast cancer-related deaths. Exploring the complex molecular pathways associated with the initiation and progression of breast cancer metastasis could lead to the discovery of more effective ways of treating the devastating phenomenon. The present review article highlights the recent advances to understand the complexity associated with breast cancer metastases, organotropism and therapeutic advances.

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Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

International Journal of Breast Cancer ◽

10.4061/2011/352182 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 45

Author(s):

Gabriel L. Fiszman ◽

María A. Jasnis

Keyword(s):

Breast Cancer ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Breast Cancers ◽

Trastuzumab Resistance ◽

Alternative Pathways ◽

Downstream Signaling ◽

Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

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Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.3.737 ◽

1996 ◽

Vol 14 (3) ◽

pp. 737-744 ◽

Cited By ~ 934

Author(s):

J Baselga ◽

D Tripathy ◽

J Mendelsohn ◽

S Baughman ◽

C C Benz ◽

...

Keyword(s):

Breast Cancer ◽

Monoclonal Antibody ◽

Metastatic Breast Cancer ◽

Growth Factor ◽

Human Cancer ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Maintenance Phase ◽

Breast Cancers ◽

Prior Therapy

PURPOSE Breast cancer frequently overexpresses the product of the HER2 proto-oncogene, a 185-kd growth factor receptor (p185HER2). The recombinant humanized monoclonal antibody (rhuMAb) HER2 has high affinity for p185HER2 and inhibits the growth of breast cancer cells that overexpress HER2. We evaluated the efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS We treated 46 patients with metastatic breast carcinomas that overexpressed HER2. Patients received a loading dose of 250 mg of intravenous rhuMAb HER2, then 10 weekly doses of 100 mg each. Patients with no disease progression at the completion of this treatment period were offered a maintenance phase of 100 mg/wk. RESULTS Study patients had extensive metastatic disease, and most had received extensive prior anticancer therapy. Adequate pharmacokinetic levels of rhuMAb HER2 were obtained in 90% of the patients. Toxicity was minimal and no antibodies against rhuMAb HER2 were detected in any patients. Objective responses were seen in five of 43 assessable patients, and included one complete remission and four partial remissions (overall response rate, 11.6%; 95% confidence interval, 4.36 to 25.9). Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in two patients, and stable disease, which occurred in 14 patients, lasted for a median of 5.1 months. CONCLUSION rhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy. This is evidence that targeting growth factor receptors can cause regression of human cancer and justifies further evaluation of this agent.

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The Metabolic Mechanisms of Breast Cancer Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2020.602416 ◽

2021 ◽

Vol 10 ◽

Author(s):

Lingling Wang ◽

Shizhen Zhang ◽

Xiaochen Wang

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Metabolic Reprogramming ◽

Breast Cancers ◽

Extrinsic Factors ◽

Intrinsic Factors ◽

Metastatic Sites

Breast cancer is one of the most common malignancy among women worldwide. Metastasis is mainly responsible for treatment failure and is the cause of most breast cancer deaths. The role of metabolism in the progression and metastasis of breast cancer is gradually being emphasized. However, the regulatory mechanisms that conduce to cancer metastasis by metabolic reprogramming in breast cancer have not been expounded. Breast cancer cells exhibit different metabolic phenotypes depending on their molecular subtypes and metastatic sites. Both intrinsic factors, such as MYC amplification, PIK3CA, and TP53 mutations, and extrinsic factors, such as hypoxia, oxidative stress, and acidosis, contribute to different metabolic reprogramming phenotypes in metastatic breast cancers. Understanding the metabolic mechanisms underlying breast cancer metastasis will provide important clues to develop novel therapeutic approaches for treatment of metastatic breast cancer.

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Obesity and Cathepsin K: A Complex Pathophysiological Relationship in Breast Cancer Metastases

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200505115132 ◽

2020 ◽

Vol 20 (8) ◽

pp. 1227-1231

Author(s):

Yaongamphi Vashum ◽

Zenith Khashim

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Cancer Metastasis ◽

Therapeutic Option ◽

Metastatic Breast ◽

Cathepsin K ◽

Skeletal Metastasis ◽

Breast Cancer Metastasis ◽

Normal Weight ◽

Breast Cancers

Background: Breast cancer appears in a strong inclination to metastasize in bone tissue. Several strategies are discussed in combating bone metastasis in breast cancer. However, therapy is only palliative and does not provide any improvement in survival to the majority of patients with advanced cancer. Obese and overweight women with breast cancer are three times more likely to develop metastatic disease compared to normal-weight women with the same treatment regimen. Overweight greatly intensify adipocytes formation in the bone marrow affecting bone metabolism by decreasing osteoblast differentiation and bone formation. Cathepsin K (CTSK), a cysteine protease, effectively degrades several components of the extracellular matrix and has the ability to differentiate adipocytes from bone marrow lineage. Therefore, the purpose of this review is to emphasize the underlying mechanism of CTSK and obesity role in breast cancer metastasis. Methods: Systematic review was performed using PubMed, EMBASE. The evidence of obesity and CTSK in breast cancer skeletal metastasis were analyzed, summarized and compared. Results: The present investigation argues for a specific association of CTSK with breast cancer skeletal metastasis by promoting adipocyte differentiation. The potential tumor-supporting roles of adipocytes are well documented, and in fact, suppressing adipocyte could be a new therapeutic option in the battle against lethal metastatic breast cancers. Conclusion: This review emphasizes CTSK through its multifaceted role in differentiating adipocytes, inflammation, and extracellular degradation, may be a critical factor in an obesity-cancer connection. Thus, integration of CTSK targeting strategies into established traditional therapies seems to hold substantial promise.

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Ca2+ Signaling as the Untact Mode during Signaling in Metastatic Breast Cancer

Cancers ◽

10.3390/cancers13061473 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1473

Author(s):

Dongun Lee ◽

Jeong Hee Hong

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Metastasis ◽

Therapeutic Potential ◽

Tumor Development ◽

Treatment Strategies ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

The Brain ◽

Ca2 Channels

Metastatic features of breast cancer in the brain are considered a common pathology in female patients with late-stage breast cancer. Ca2+ signaling and the overexpression pattern of Ca2+ channels have been regarded as oncogenic markers of breast cancer. In other words, breast tumor development can be mediated by inhibiting Ca2+ channels. Although the therapeutic potential of inhibiting Ca2+ channels against breast cancer has been demonstrated, the relationship between breast cancer metastasis and Ca2+ channels is not yet understood. Thus, we focused on the metastatic features of breast cancer and summarized the basic mechanisms of Ca2+-related proteins and channels during the stages of metastatic breast cancer by evaluating Ca2+ signaling. In particular, we highlighted the metastasis of breast tumors to the brain. Thus, modulating Ca2+ channels with Ca2+ channel inhibitors and combined applications will advance treatment strategies for breast cancer metastasis to the brain.

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Metastatic breast cancer in regrowth of thyroid lobe after subtotal thyroidectomy – case report

Polish Journal of Surgery ◽

10.5604/01.3001.0013.5723 ◽

2019 ◽

Vol 92 (5) ◽

pp. 1-3

Author(s):

Joanna Pakuła ◽

Tomasz Stępień ◽

Krzysztof Kuzdak

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Metastasis ◽

Malignant Neoplasm ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Thyroid Lobe ◽

Total Recovery ◽

Oncological Treatment ◽

The Right

Breast cancer is the most common malignant neoplasm among women. Metastases to the thyroid are relatively rare. Those lesions annunciate neoplasm dissemination in most cases. Metastatic breast cancer of thyroid lobe regrowth hasn’t been described yet. In the article the authors present a case of a 66-year old women with isolated, metachronous breast cancer metastasis in regrowth of the right thyroid lobe. Resection of the right lobe with metastatic tumor was performed with a purpose of total recovery. Despite surgery, multiple bone metastases were detected a few months after. In conclusion, regrowth of the thyroid is a potential site of recurrence and metastasis. Therefore, the thyroid bed cannot be omitted in routine examination during and after oncological treatment.

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WNK1 Enhances Migration and Invasion in Breast Cancer Models

10.1101/2021.03.09.434610 ◽

2021 ◽

Author(s):

Ankita B. Jaykumar ◽

Jiung Jung ◽

Pravat Parida ◽

Tuyen T. Dang ◽

Magdalena Grzemska ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Migration And Invasion ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Collagen Matrices ◽

Cancer Models ◽

Protein Components

AbstractMetastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

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