Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

Zambrano, Joelle N.; Neely, Benjamin A.; Yeh, Elizabeth S.

doi:10.1016/j.phrs.2017.02.007

Cited by 5 publications

(14 citation statements)

References 47 publications

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“…[26] Additionally, Brd4 is associated with drug resistant HER2+/ErbB2+ breast cancer types. [27] On the other hand, we were unable to find an association with breast cancer for COLQ (Collagen Like Tail Subunit of Asymmetric Acetylcholinesterase). Therefore, COLase3 proteomics on single FFPE tissue sections both accurately reports tissue regulators of breast cancer and may also predict new topics for breast cancer research.…”

Section: Resultsmentioning

confidence: 80%

Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI–Imaging Mass Spectrometry

Angel

Schwamborn²,

Comte‐Walters

et al. 2018

Proteomics Clinical Apps

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Purpose We recently reported a new method accessing proteins from extracellular matrix by imaging mass spectrometry (ECM IMS). ECM IMS was evaluated for use in exploring breast tissue pathologies. Experimental Design A tissue microarray (TMA) was analyzed that had 176 cores of biopsies and lumpectomies spanning breast pathologies of inflammation, hyperplasia, fibroadenoma, invasive ductal carcinoma and invasive lobular carcinoma and normal adjacent to tumor (NAT). NAT was compared to subtypes by area under the receiver operating curve (ROC) >0.7. A lumpectomy was also characterized for collagen organization by microscopy and stromal protein distribution by IMS. LC-based high-resolution accurate mass (HRAM) proteomics was used to identify proteins from the lumpectomy. Results TMA analysis showed distinct spectral signatures reflecting a heterogeneous tissue microenvironment. Ninety-four peaks showed a ROC >0.7 compared to NAT; NAT had overall higher intensities. Lumpectomy analysis by IMS visualized a complex central tumor region with distal tumor regions. HRAM LC-based proteomics identified 39 stromal proteins. Accurate mass matches between image data and LC-based proteomics demonstrated a heterogeneous collagen type environment in the central tumor. Conclusions Data portray the heterogeneous stromal microenvironment of breast pathologies, including alteration of multiple collagen type patterns. ECM IMS is a promising new tool for investigating the stromal microenvironment of breast tissue including cancer.

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Section: Resultsmentioning

confidence: 80%

Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI–Imaging Mass Spectrometry

Angel

Schwamborn²,

Comte‐Walters

et al. 2018

Proteomics Clinical Apps

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“…Prior studies showed that HUNK downregulates expression of the tumor suppressor p27 by preventing nuclear accumulation of p27 [ 6 , 7 ]. Therefore, to further evaluate the potential effect of STU on HUNK function, we next assessed p27 expression and localization in SMF cells after STU treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Preclinical studies have indicated HUNK’s potential as a novel therapeutic target in HER2+ breast cancer [ 6 , 7 , 9 , 10 ]. To date, HUNK inhibition has been accomplished either through the use of shRNA to decrease HUNK expression, or through the use of kinase-inactive HUNK mutants, such as K91M HUNK [ 6 , 8 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase

et al. 2018

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HUNK is a protein kinase that is implicated in HER2-positive (HER2+) breast cancer progression and resistance to HER2 inhibitors. Though prior studies suggest there is therapeutic potential for targeting HUNK in HER2+ breast cancer, pharmacological agents that target HUNK are yet to be identified. A recent study showed that the broad-spectrum kinase inhibitor staurosporine binds to the HUNK catalytic domain, but the effect of staurosporine on HUNK enzymatic activity was not tested. We now show that staurosporine inhibits the kinase activity of a full length HUNK protein. Our findings further suggest that inhibiting HUNK with staurosporine has a strong effect on suppressing cell viability of HER2/neu mammary and breast cancer cells, which express high levels of HUNK protein and are dependent on HUNK for survival. Significantly, we use in vitro and in vivo methods to show that staurosporine synergizes with the HER2 inhibitor lapatinib to restore sensitivity toward HER2 inhibition in a HER2 inhibitor resistant breast cancer model. Collectively, these studies indicate that pharmacological inhibition of HUNK kinase activity has therapeutic potential for HER2+ breast cancers, including HER2+ breast cancers that have developed drug resistance.

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Section: Introductionmentioning

confidence: 99%

“…Hormonally upregulated neu-associated kinase (HUNK) is an approximately ~80 kDa serine/threonine (S/T) protein kinase that has been reported to be expressed in about 50% of breast carcinomas [ 1 , 2 , 3 , 4 ]. HUNK is part of the AMP-associated protein kinase (AMPK) family and plays a role in a variety of cellular processes, including the regulation of cell survival, proliferation, and autophagy [ 1 , 5 ]. While this protein was originally discovered in mouse mammary glands and is expressed in breast tissue, it has also been found in other organ systems such as the brain and central nervous system, and plays a role in diseases including colon cancer [ 3 , 4 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

HUNK Gene Alterations in Breast Cancer

et al. 2022

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Hormonally upregulated neu-associated kinase (HUNK) is a serine/threonine (S/T) protein kinase related to the adenosine monophosphate-activated protein kinase (AMPK) family of kinases. HUNK was originally discovered using a screen to identify kinases expressed in the mouse mammary gland. Therefore, the majority of studies to date have been carried out in models specific to this tissue, and the kinase was named to reflect its mammary gland-specific physiology and pathology. Prior studies show a clear pathogenic role for HUNK in breast cancer. HUNK is upregulated in response to oncogenic HER2/neu and Akt, and there is strong evidence that HUNK is critical for the survival of breast cancer cells. Further evidence shows that inhibiting HUNK using a variety of breast cancer models, including those that are resistant, inhibits tumorigenesis and metastasis. However, HUNK alterations are infrequent. Here, the incidence and consequence of HUNK alterations in breast cancer is reviewed using data mined from the online database cBioPortal and considered in relation to prior research studies.

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Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

Cited by 5 publications

References 47 publications

Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI–Imaging Mass Spectrometry

Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI–Imaging Mass Spectrometry

Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase

HUNK Gene Alterations in Breast Cancer

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