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Using MC1R Genotype to Impact Skin Cancer Risk Behaviors in Hispanics/Latinos - Peter Kanetsky, PhD (Moffitt) and Brenda Soto, PhD (PHSU)

Understanding how Mitotic Kinases Drive EMT in Breast CancersSrikumar S. Chellappan PhD (Moffitt) and Harold Saavedra PhD (PHSU)

Adrenergic Modulation of Ovarian Cancer Progression and ChemoresistanceAlvaro Monteiro, PhD; Heather Jim, PhD (Moffitt) and Guillermo Armaiz-Peña, PhD (PHSU)


Using MC1R Genotype to Impact Skin Cancer Risk Behaviors in Hispanics/Latinos - Peter Kanetsky, PhD (Moffitt) and Brenda Soto, PhD (PHSU)

Numbers of skins cancers, including melanoma, and squamous and basal cell carcinoma are on the rise among Hispanic/Latinos (H/L).  Limiting exposure to the sun and artificial sources of ultraviolet radiation and having routine skin examinations can help reduce morbidity and mortality resulting from skin cancers.  Genetic variation in a gene called the melanocortin-1 receptor (MC1R) is a good indicator of risk of skin cancer, and this holds true for individuals who do not easily burn, have a tendency to tan, have darker hair color, and/or have fewer freckles.  To determine whether knowledge and feedback of MC1R genotype can play a role in the promotion of behaviors linked to risk reduction and early detection of skin cancers, we will recruit 400 H/L participants from Ponce, Puerto Rico and 400 from Tampa, Florida.  Study participants will receive mailed health education materials containing either i) generic information about skin cancer risk, risk reduction and early detection or ii) personalized (precision) genetic information about skin cancer risk, risk reduction and early detection anchored in results from MC1R genotyping.  Participants will then be asked questions about prevention behaviors after three months and again after nine months.  The results of this project will help inform whether genetic screening targeted to the general H/L population of can positively influence risk behaviors associated with skin cancer.

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Understanding how Mitotic Kinases Drive EMT in Breast Cancers - Srikumar S. Chellappan PhD (Moffitt) and Harold Saavedra PhD (PHSU)

Americans of Hispanic and African heritage are at higher risk to develop molecular subtypes of breast cancer that associate with poor prognosis, including triple-negative (ER-PR-Her2-) and Her2+ breast cancers relative to Non-Hispanic whites.  Increased chromosome instability (CI) in most cancers correlates with poor clinical outcomes and higher levels of CI is observed in poor-prognosis HR- breast cancers relative to luminal subtypes.  Centrosome amplification, or the accumulation of 3 or more centrosomes within a cell, and defective mitosis are two principal drivers of chromosome instability.  Centrosome amplification correlates with invasion, metastasis, poor clinical outcomes, and HR- subtypes. Interestingly, we identified TTK and TBK1 kinases as regulators of centrosome amplification in cancer cells.  TTK and TBK1 are centrosome/mitotic regulators, and our preliminary data show that these two mitotic kinases can significantly influence epithelial to mesenchymal transition (EMT), an activity never described for mitotic kinases.  Silencing of TTK reduces phosphorylation of SMAD3 upon TGF-b stimulation, suppressing regulators of EMT.  In a similar fashion, recent studies from the Chellappan lab identified TBK1 physically interacts with the E2F1 transcription factor, which induces the expression of TTK, and EMT genes like vimentin, fibronectin, ZEB-1, and ZEB2.  Further, depletion of TBK1 could significantly reduce the expression of MMP2 and MMP9, suggesting that kinases involved in mitosis like TTK and TBK1 can contribute significantly to the EMT and metastasis of tumors Since inhibitors are available for TTK and TBK1, it would be feasible to target these kinases to combat HR- breast cancers. This project proposes to examine if elevated levels and activity of TTK and TBK1 enhance tumor growth, epithelial to mesenchymal transition (EMT) and metastasis, and that such events correlate with prognostic molecular subtypes and survival outcomes of H/L breast cancer patients from Puerto Rico. Data resulting from this project will allow the identification of pathways influenced by mitotic regulators in breast cancer cells driving invasion and metastasis, and will provide potential prognostic markers for high-risk breast tumors in Hispanics/Latinos.               

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Adrenergic Modulation of Ovarian Cancer Progression and Chemoresistance - Alvaro Monteiro, PhD; Heather Jim, PhD (Moffitt) and Guillermo Armaiz-Peña, PhD (PHSU)

There is growing evidence for the role of stress in cardiovascular pathologies, cancer, and other diseases. Work from our group and others has shown that psychological states such as chronic stress or depression may accelerate growth of existing tumors and promote chemoresistance. Importantly, a significant number of ovarian cancer patients are clinically depressed or lack social support. These emotional states have been linked to sustained activation of the sympathetic nervous system and decreased survival. Our group has shown that activation of the sympathetic nervous system leads to increased levels of norepinephrine and epinephrine in the tumor microenvironment and ovarian cancer progression by inducing pro-tumoral pathways. Our preliminary data in cancer cell lines suggest that norepinephrine significantly changes the expression of genes implicated in ovarian cancer and attenuates cisplatin-induced ovarian cancer cell apoptosis.  Given the importance of BRCA1-regulated DNA repair mechanisms in cisplatin response, adrenergic regulation of BRCA1 expression in tumors may also impact ovarian cancer progression and resistance to platinum-based therapy. However, the underlying mechanisms behind these observations are not completely understood. In this pilot we will test this hypothesis by achieving the following aims: 1) To dissect the effects of adrenergic signaling in ovarian cancer cells and 2) To explore the association between perceived stress and depressive symptomatology with tumor catecholamines, DNA damage, and BRCA1 protein expression. This proposal provides a unique approach to explore the link between stress and ovarian cancer outcomes at both the tumor level and the patient level. This proposal will provide the groundwork for additional research on precision medicine by linking psychological risk factors with underlying tumor biology.

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