Purnima K. Wagh's research while affiliated with Cincinnati Children's Hospital Medical Center and other places

Publications (15)

Article
Full-text available
The Ron receptor is overexpressed in human breast cancers and is associated with heightened metastasis and poor survival. Ron overexpression in the mammary epithelium of mice is sufficient to induce aggressive mammary tumors with a high degree of metastasis. Despite the well-documented role of Ron in breast cancer, few studies have examined the nec...
Article
Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of-function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm, pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological process...
Article
Full-text available
Disease progression and recurrence are major barriers to survival for breast cancer patients. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly overexpressed breast cancer oncogenes, Ron (Recepteur d...
Article
A standard therapy for breast cancer is the use of receptor tyrosine kinase (RTK) inhibitors. RTKs efficiently target multiple receptors, including the Ron transmembrane receptor, whose activation leads to increased survival, migration, and angiogenesis through signaling pathways such as PI3K/Akt and NF-κB. Ron overexpression is correlated with inc...
Article
The Ron receptor tyrosine kinase (macrophage stimulating 1 receptor) is overexpressed in approximately 50% of human breast cancers. Transgenic mice overexpressing Ron in the mammary epithelium [mouse mammary tumor virus driven (MMTV)-Ron expressing mice] develop mammary tumors that exhibit up-regulation of β-catenin and β-catenin target genes. β-Ca...
Article
Full-text available
The Ron receptor tyrosine kinase (TK) is overexpressed in many cancers, including prostate cancer. To examine the significance of Ron in prostate cancer in vivo, we utilized a genetically engineered mouse model, referred to as TRAMP mice, that is predisposed to develop prostate tumors. In this model, we show that prostate tumors from 30-week-old TR...
Article
Full-text available
Our previous studies demonstrated that selective overexpression of the Ron receptor tyrosine kinase in the murine mammary epithelium leads to mammary tumor formation. Biochemical analysis of mammary tumor lysates showed that Ron overexpression was associated with increases in β-catenin expression and tyrosine phosphorylation. β-Catenin has also bee...
Article
Full-text available
Breast cancer is a major cause of cancer-related deaths in American women; therefore, the identification of novel breast cancer-related molecules for the discovery of new markers and drug targets remains essential. The human DEK gene, which encodes a chromatin-binding protein and DNA topology regulator, is upregulated in many types of cancer. DEK h...
Article
Full-text available
Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol...
Article
The CHEK2 (Chk2 in mice) polymorphic variant, CHEK2*1100delC, leads to genomic instability and is associated with an increased risk for breast cancer. The Ron receptor tyrosine kinase is overexpressed in a large fraction of human breast cancers. Here, we asked whether the low penetrance Chk2*1100delC allele alters the tumorigenic efficacy of Ron in...
Article
Full-text available
The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulating-protein (HGFL). HGFL is primarily synthesized and secreted from hep...

Citations

... The RON receptor tyrosine kinase is expressed at low levels in epithelial cells and macrophages and is phenotypically responsible for signals to promote wound healing and the resolution of inflammation [1][2][3]. RON upregulation has significant oncogenic implications promoting cell growth, survival, migration, recruitment of pro-tumor immune cells, and suppression of anti-tumor immunity [4][5][6][7][8][9]. Hepatocyte growth factor-like (HGFL) protein, the RON ligand, ligates to two RON homodimers, leading to conformational changes that induce autophosphorylation of the tyrosine kinase (TK) domain and subsequent activation of a plethora of downstream signaling pathways [6,10,11]. ...
... It is involved in many processes, including lung development, maintenance of stem cells, cell cycle progression, and tumorigenesis. 22 Individuals with pathogenic variants in DICER1 are at increased risk of certain malignancies including PPBs, cystic nephroma, thyroid nodules, ovarian Sertoli-Leydig Cell tumor, thoracic embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, genitourinary sarcomas, neuroendocrine tumors, pineoblastoma, pituitary blastoma, Wilms tumor, multinodular goiter, and several other sarcomas. 7,23 Approximately 70% of all patients with PPB harbor germline mutations in DICER1 that can be identi ed with standard clinical testing. ...
... Thus, RON is an exciting target for the interrogation of recurrence biology, development of robust signatures predictive of recurrence, and is a prospective therapeutic target for the treatment or prevention of recurrent disease. The chromatin associated oncogene, DEK, is a RON-stimulated protein that promotes tumor cell proliferation [8]. Both RON and DEK have been shown to augment breast cancer stem cells, a subpopulation of treatment evading, tumor-initiating cells implicated in cancer recurrence [9,10]. ...
... Both RON and DEK have been shown to augment breast cancer stem cells, a subpopulation of treatment evading, tumor-initiating cells implicated in cancer recurrence [9,10]. Mechanistically, RON and DEK promote β-catenin activation through independent mechanisms that synergize to support breast cancer stem cell self-renewal and breast cancer metastasis in preclinical models [8][9][10][11][12][13]. ...
... In addition, aberrant activation of the receptor has been described in many solid tumors. These include pancreas, lung, liver, breast, colon, prostate, bladder, and ovarian cancers, as well as AML and Burkitt lymphoma [13][14][15][16][17][18][19][20][21][22][23][24][25]. RON activation contributes to tumor progression and metastasis by promoting cell proliferation, motility, and inhibiting apoptosis. ...
... Both RON and DEK have been shown to augment breast cancer stem cells, a subpopulation of treatment evading, tumor-initiating cells implicated in cancer recurrence [9,10]. Mechanistically, RON and DEK promote β-catenin activation through independent mechanisms that synergize to support breast cancer stem cell self-renewal and breast cancer metastasis in preclinical models [8][9][10][11][12][13]. ...
... The chromatin associated oncogene, DEK, is a RON-stimulated protein that promotes tumor cell proliferation [8]. Both RON and DEK have been shown to augment breast cancer stem cells, a subpopulation of treatment evading, tumor-initiating cells implicated in cancer recurrence [9,10]. Mechanistically, RON and DEK promote β-catenin activation through independent mechanisms that synergize to support breast cancer stem cell self-renewal and breast cancer metastasis in preclinical models [8][9][10][11][12][13]. ...
... Tumoral RON expression correlates with increased BCa progression, metastasis, and poor prognosis independent of molecular subtype [8,10,27,28]. RON activation leads to downstream activation of several signaling cascades that promote pleiotropic functions, including cell proliferation, invasion, angiogenesis, therapeutic resistance, and stemness [8,10,27,29,30]. Several gain and lossof-function mouse models have established RON upregulation in epithelial cells as a key driver of mammary tumorigenesis [31,32] while global RON or HGFL knockout in BCa [27,33] abrogates tumorigenesis. ...
... 3.5. USP39 is positively correlated to CHK2 in clinical lung cancer samples CHK2 has been identified as a tumor suppressor, which is mutated or depleted in various cancers, including breast, colon, bladder, ovary and prostate carcinomas, albeit at low frequencies [49][50][51][52]. Besides mutated in cancer, low level of CHK2 was also observed in lung cancers, which contributes to chemo-radiation resistance [53][54][55]. ...
... LAMP2a is manifested to be activated by various external stressors in TME, such as hypoxia and androgen deprivation [68]. e RON receptor (MST1R), a Met tyrosine kinase receptor family member, exists preferentially in prostate epithelial cells and macrophages [69,70]. Prior work demonstrated macrophage-intrinsic RON as a negative regulator of macrophage activation. ...