Paraic A Kenny

• PhD
• Chair at Gundersen Health System

Background Growth factor receptor‐bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR, and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration, and invasion through its large repertoire of protein–prote...

Growth factor receptor-bound 7 (Grb7) is an adaptor protein implicated in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration and invasion through its large repertoire of protein-protein interact...

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stal...

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stal...

GATA3 is somatically mutated in approximately 15% of estrogen receptor positive human breast tumors, however the mechanism(s) by which these alterations contribute to tumorigenesis are unclear. The observed patterns of mutations suggest a strong selective pressure to mutate a single allele of GATA3 in a manner favoring retention of the first of two...

Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit monoclonal antibody, GMF-1A3, that selectively recognizes the cell-associated cleaved Amphiregulin epit...

Background : While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate infection and transmission risks within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a hospital-based outpatient ESRD facility over 13 days in the second quarter of 2021, an...

The EGFR ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently inter...

Background While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate the risk of infection and transmission within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a 13-day period in the second quarter of 2021 in a hospital-based ESRD facility, and...

Amphiregulin (AREG) is a transmembrane protein which, following TACE/ADAM17-dependent cleavage, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. Expression of Amphiregulin has been described by immunohistochemistry in several tumor types, including lung, prostate, head and...

The implementation of monoclonal antibody therapeutics during the COVID-19 pandemic altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for resistant variants. Within-host viral evolution was reported in treated immunocompromised individuals but whether this signifies a real risk of onward transmission is...

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stal...

Background The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transme...

The implementation of monoclonal antibody therapeutics during the COVID19 pandemic has altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for variants resistant to one or more monoclonal antibodies and subsequent transmission into the wider population. Early studies indicated that monoclonal antibody tre...

While considerable success has been achieved with treating BRAF-V600E mutant tumors in several organ systems, tumors expressing non-V600E BRAF mutations remain a significant clinical challenge. Such atypical BRAF mutations are classified based on their kinase activity, RAS-dependence and their requirement for dimerization to function. We identified...

Background: The COVID-19 pandemic poses a particularly high risk for End Stage Renal Disease (ESRD) patients so rapid identification of case clusters in ESRD facilities is essential. Nevertheless, with high community prevalence, a series of ESRD patients may test positive contemporaneously for reasons unrelated to their shared ESRD facility. Here w...

Background: BRAF, when mutated at V600E, is a potent oncogenic driver in melanoma, lung and colorectal cancer with well understood signaling mechanisms and established treatment guidelines. Non-V600E mutations are less common, more functionally diverse and do not yet have clear treatment guidelines. One class of non-V600E mutations are BRAF fusion...

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stal...

Background: The COVID-19 pandemic of 2020 poses a particularly high risk for End Stage Renal Disease (ESRD) patients and led to a need for facility-wide control plans to prevent introduction and spread of infection within ESRD facilities. Rapid identification of clusters of contemporaneous cases is essential, as these may be indicative of within-fa...

College reopening decisions during the SARS-CoV-2 pandemic represent a trade-off between competing risks to students, faculty and staff, and college finances. Additionally, risks taken in reopening colleges can impose significant burdens on individuals living in surrounding communities. Many colleges that reopened for in-person instruction have rep...

SARS-CoV-2 spread has proven to be especially difficult to mitigate in high risk settings, including nursing homes, cruises, prisons and various industrial settings. Among industrial settings, meat processing facilities in the United States have experienced particularly challenging outbreaks. We have sequenced SARS-CoV-2 whole viral genomes from in...

Purpose: The epidermal growth factor receptor ligand, Amphiregulin, is a transcriptional target of estrogen receptor alpha and is required for pubertal mammary gland development. Previous studies using immortalized human breast cancer cell line xenografts have suggested that Amphiregulin may be an important effector of estrogen receptor alpha duri...

Background Targeting of somatic MET mutations using crizotinib has led to strong clinical responses, most frequently in patients with lung cancer, raising the possibility of adopting similar treatment strategies in patients with MET alterations in other cancer types. Patient and Methods We describe a patient with advanced triple-negative breast ca...

As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these amplified genes, if any, might be driving tumor growth and might thus be worth considering targeting can...

p>Crizotinib is FDA approved in lung cancers with alterations in MET, ROS1 or ALK. Alterations in these genes are also reported in breast cancer, but are very rare and not routinely evaluated. Here we describe two heavily pre-treated patients with metastatic breast cancer treated with off-label single-agent crizotinib following NGS panel detection...

As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these amplified genes, if any, might be driving tumor growth and might thus be worth considering targeting can...

Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing the optimal sequencing of these agents in larger patient cohorts, but successful long-term indiv...

Approximately 266,000 women will be newly diagnosed with invasive breast cancer in the US this year, making it the most prevalent cancer in females, resulting in a 1 in 8 lifetime risk. Many of these tumors are of the hormone receptor positive luminal subtype, with 60-80% expressing the estrogen and/or progesterone receptor (ER+/PR+). The transcrip...

At our center, a standard 25 gene panel has proved useful for the identification of pathogenic germline mutations in many families with a high penetrance of breast and ovarian cancer, yet there remain several families with very high cancer incidence but from whom these assays have not identified pathogenic alleles. To attempt to define the genetic...

mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K...

Background Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, is not only essential for proper mammary ductal development, but also associated with breast cancer proliferation and growth. In the absence of AREG, mammary ductal growth is stunted and fails to expand. Furthermore, suppression of AREG expression in estrogen receptor...

Background/aim: GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in...

Resistance to current therapies still impacts a significant number of melanoma patients and can be regulated by epigenetic alterations. Analysis of global cytosine methylation in a cohort of primary melanomas revealed a pattern of early demethylation associated with overexpression of oncogenic transcripts. Loss of methylation and associated overexp...

Amphiregulin (AREG) is an estrogen-responsive ligand of the epidermal growth factor receptor. Mice with germline deletion of AREG are defective in pubertal mammary expansion. Using shRNA, we have previously reported that the estrogen-responsive growth of MCF7 xenograft tumors in immunocompromised mice is also AREG-dependent. Here we use a series of...

The MET proto-oncogene encodes a receptor tyrosine kinase which is activated by Hepatocyte Growth Factor binding. Recent reports have described single agent activity for crizotinib in MET-amplified or mutant lung adenocarcinoma, squamous cell carcinoma and papillary renal cell carcinoma. Here we describe a stage IV triple-negative breast cancer pat...

Epigenetic changes in cancer are thought to contribute to the regulation of invasion and metastasis. To study this at a genome-wide level in melanoma, we analyzed the methylome of 44 cases of malignant melanoma. We saw widespread demethylation occurring preferentially outside of CpG islands. Comparison of primary and metastatic lesions showed demet...

Unlike humans, inbred genetically engineered mice have minimal inter-individual variation and, consequently, offer substantially increased statistical power for robust definition of recurrent cooperating cancer mutations. While technically feasible, whole exome sequencing is expensive and extremely data-intensive. Somatic mutation analysis using pa...

The MET proto-oncogene encodes a receptor tyrosine kinase which is activated by Hepatocyte Growth Factor binding. Recent reports have described single agent activity for crizotinib in MET-amplified or mutant lung adenocarcinoma, squamous cell carcinoma and papillary renal cell carcinoma. Here we describe a stage IV triple-negative breast cancer pat...

AbstractAmphiregulin (AREG) is an estrogen-responsive ligand of the epidermal growth factor receptor. Mice with germline deletion of AREG are defective in pubertal mammary expansion. Using shRNA, we have previously reported that the estrogen-responsive growth of MCF7 xenograft tumors in immunocompromised mice is also AREG-dependent. Here we use a s...

Aims: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. Materials and methods: Cell viability and migrati...

Purpose: Precision oncology develops and implements evidence-based personalized therapies that are based on specific genetic targets within each tumor. However, a major challenge that remains is the provision of a standardized, up-to-date, and evidenced-based precision medicine initiative across a geographic region. Materials and methods: We dev...

Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic combinations. As such, tumor recurrence is high and patient prognosis is poor. GRB7 is a cytoplasmic adap...

The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overe...

The rate of ultra-late recurrence (beyond 10-15 years) of cutaneous melanoma has been estimated to be between 2.0-6.9% from large case series. Two major factors complicate the interpretation of these data. Firstly, the risk of second primary melanoma is approximately 5% creating uncertainty about whether at least some of these late onset tumors mig...

Epigenetic changes in cancer are thought to contribute to regulation of invasion and metastasis. To study this at a genome-wide level in melanoma we analyzed the methylome of 44 cases of malignant melanoma. We saw widespread demethylation in melanoma occurring preferentially outside of CpG islands. Comparison of primary and metastatic lesions showe...

Ultra-late melanoma recurrence is infrequent, poorly understood and, in most cases, difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30 year disease-free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. Here we report t...

GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen...

GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen...

Epigenetic changes in cancer are thought to contribute to regulation of invasion and metastasis. To study this at a genome-wide level in melanoma we analyzed the methylome of 44 cases of malignant melanoma with the HELP (HpaII tiny fragment enriched by LM-PCR) assay and compared it to melanocyte controls. We saw widespread demethylation in melanoma...

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERα)-positive breast cancer. Many ERα target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts a...

Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelial-mesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca(2+) signaling via purinergic receptors is associated with epidermal growth factor (EGF)-in...

The GATA3 transcription factor is expressed in luminal breast epithelial cells and is required for mammary gland development. Recent reports indicate that somatic mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors. Our analysis of these published data demonstrates that the human breast tumors with GATA3 mutations are...

Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic cocktails. As such, tumor recurrence is high and patient prognosis is poor. GRB7 is a soluble adaptor pro...

Approximately 70% of breast cancer cases are Estrogen Receptor (ER) positive. In many cases, these patients are well-served by endocrine therapies such as tamoxifen and aromatase inhibitors, however the emergence of endocrine-resistant disease in up to 40% of these patients is a major clinical concern. This necessitates treatment with more toxic ch...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Estrogen is an essential hormone for mammary gland development and is a key driver of proliferation during the development of estrogen receptor positive breast tumors. The actions of estrogen are primarily mediated by its receptor, the ERα transcription factor, which...

Epigenetic alterations can direct carcinogenesis by leading to transcriptional changes and inducing genomic instability. We analyzed the methylome of malignant melanoma and observed widespread loss of DNA methylation that was found to preferentially occur outside of CpG islands. Demethylation was seen to occur early during carcinogenesis, was indep...

Epigenetic changes in cancer are thought to contribute to regulation of tumor invasion and metastasis, but this previously has not been studied at a genome wide level in melanoma. We analyzed the methylome of 44 cases of malignant melanoma with the HELP (HpaII tiny fragment enriched by LM-PCR) assay and compared it with healthy melanocyte controls....

The Epidermal Growth Factor Receptor (EGFR) is frequently expressed in triple-negative breast cancer and is a marker of poor prognosis. We have also recently identified an EGFR-associated adaptor protein, GRB7, as being associated with reduced relapse-free survival in triple-negative breast cancer. In this study we have sought to define the mechani...

Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via RARγ-mediated regulation of tumor cell transcription. Since topical retinoids can cause adverse cutaneous effects and since tumors can develop resis...

GATA3 is an essential mediator of mammary gland development and is expressed at high levels in Estrogen Receptor positive tumors. This gene has recently emerged as one of the most frequently mutated genes in Estrogen Receptor positive breast cancer. GATA3 mutant tumors tend to retain and express the wild-type GATA3 allele which, together with the e...

Breast cancer is a heterogeneous disease associated with variable clinical outcomes despite standard local therapy for the primary tumor and systemic adjuvant therapy to prevent distant recurrence. Management decisions are typically made using classical prognostic and predictive clinicopathologic factors, and more recently gene expression profiling...

Bisected, complex N-glycans on glycoproteins are generated by the glycosyltransferase MGAT3 and cause reduced cell surface binding of galectins. Previously, we showed that MGAT3 reduces growth factor signaling and retards mammary tumor progression driven by the Polyoma middle T antigen (PyMT) expressed in mammary epithelium under the MMTV promoter....

Increased expression of HBEGF in estrogen receptor-negative breast tumors is correlated with enhanced metastasis to distant organ sites and more rapid disease recurrence upon removal of the primary tumor. Our previous work has demonstrated a paracrine loop between breast cancer cells and macrophages in which the tumor cells are capable of stimulati...

Expression of the Epidermal Growth Factor Receptor ligand, Amphiregulin, has been associated with estrogen receptor positive breast cancer. As Amphiregulin is proteolytically released from the surface of breast cancer cells, we investigated the levels of Amphiregulin in the serum of breast cancer patients and cancer-free women to evaluate its poten...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Triple-negative breast cancers (TNBC) lack expression of Estrogen Receptor, Progesterone Receptor, and HER2 and, as such, are non-responsive to currently available targeted therapies. Thus, more insight is needed into the molecular mechanisms underlying this disease in ord...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Despite advances in screening and prevention, breast cancer is still associated with a high mortality rate that predominantly results from the development of metastatic disease. One of the key steps of the metastatic cascade is invasion. Previous work in our lab has discov...

Amphiregulin (AREG), a ligand for Epidermal Growth Factor Receptor (EGFR), has been implicated as an effector of ERα signaling in mammary gland development and as a candidate ERα effector in human breast cancers. Analysis of 13 luminal subtype breast cancer cell lines and human breast tumors showed a strong correlation between ERα status and high A...

The Epidermal Growth Factor Receptor is frequently expressed in triple-negative breast cancer and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the...

Breast cancer is a heterogeneous disease associated with variable clinical outcomes despite standard local therapy for the primary tumor and systemic adjuvant therapy to prevent distant recurrence. Management decisions are typically made using classical prognostic and predictive clinicopathologic factors, and more recently gene expression profiling...

The microenvironment where a tumor originates plays an important role in its initiation, growth, progression and metastatic capability. Since in most cancers the microenvironment is not derived from the malignant clone and does not contain oncogenic mutations, it is likely that the tumor microenvironment is reprogrammed epigenetically to support th...

Key Points We observed that SMAD7, a negative regulator of TGF-β receptor-I kinase, is markedly reduced in MDS, and leads to ineffective hematopoiesis. Increased levels of microRNA-21 are seen in MDS and reduce SMAD7 levels, thus overactivating TGF-β signaling.

The local microenvironment influences tumor progression in several important ways. A recent study by Nguyen-Ngoc and colleagues used explants of primary human and mouse mammary tumors to examine how the composition of the extracellular matrix modulates tumor cell invasion. Culture in the presence of a three-dimensional laminin-rich basement membran...

GATA3 is expressed in normal luminal breast epithelial cells and is a key transcription factor in mammary gland development. In human breast tumors, high GATA3 protein levels are associated with estrogen receptor (ER) positivity and low grade. Recent published reports indicate that somatic mutations of GATA3 occur in up to 21% of ER+ tumors. These...

Introduction Metastasis of breast cancer is the main cause of death in patients. Previous genome-wide studies have identified gene-expression patterns correlated with cancer patient outcome. However, these were derived mostly from whole tissue without respect to cell heterogeneity. In reality, only a small subpopulation of invasive cells inside the...

Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells int...

Amphiregulin, like other ErbB ligands, is synthesized as a pro-protein which requires cleavage at the cell surface to release the active signaling domain. Prior studies using a variety of approaches have not yielded a consensus about the precise cleavage site. Here we report the purification and protein sequencing of the cell-associated human Amphi...

Calcium signaling is a critical regulator of cell proliferation. Elevated expression of calcium channels and pumps is a characteristic of some cancers, including breast cancer. We show that the plasma membrane calcium channel TRPV6, which is highly selective for Ca(2+), is overexpressed in some breast cancer cell lines. Silencing of TRPV6 expressio...

Plasma membrane calcium ATPases (PMCAs) actively extrude Ca2+ from the cell and are essential components in maintaining intracellular Ca2+ homeostasis. There are four PMCA isoforms (PMCA1–4), and alternative splicing of the PMCA genes creates a suite of calcium efflux pumps. The role of these different PMCA isoforms in the control of calcium-regula...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The majority of breast cancer deaths are due to the development of metastatic disease. The metastatic cascade consists of a series of steps and includes primary tumor growth and angiogenesis, invasion, intravasation, cell survival in circulation, extravasation and sustai...

About 70% of breast cancers are estrogen receptor positive (ER+) and current treatments target either ER activity (Tamoxifen and Fulvestrant) or the production of estrogen (aromatase inhibitors). These treatments have led to significant increases in disease-free and overall survival, but after initial response to these agents, many ER+ cancers prog...