Aggressive Form of Breast Cancer Influenced by Dual Action of Genes and RNA

Latina women are typically diagnosed with aggressive triple-negative breast cancer at late stages and could benefit from treatments targeted to the biology of their disease.


Newswise — WASHINGTON — Women with an aggressive, less-common type of breast cancer, known as triple-negative, versus a more common form of the disease, could be differentiated from each other by a panel of 17 small RNA molecules that are directly influenced by genetic alterations typically found in cancer cells.

Researchers lead by Luciane Cavalli, PhD, at Georgetown Lombardi Comprehensive Cancer Center, and colleagues found that variations in how these small RNA, known as microRNA (miRNA), are expressed, at higher or lower levels, could partially explain disparate rates of triple-negative breast cancer (TNBC) in Latina women compared to non-Hispanic white women and potentially lead to more effective treatment options.

That is the finding of a new study that was published October 22, 2019, in Oncotarget.

“Due to the variability in expression of miRNA by race or ethnicity, we determined that it was critical to characterize the genomic lineage (or ancestral background) of women with TNBC,” said Cavalli, an adjunct professor of medicine at Georgetown University School of Medicine and a faculty member at Instituto de Pesquisa Pelé Pequeno Príncipe in Brazil. “While our focus was on genetics, we remain aware that non-genetic factors, such as social-economic conditions, can significantly impact the incidence rates of TNBC and other subtypes of breast cancer.” 

Statisticians estimate that TNBC occurs in up to one-third of women in Latin American countries, a rate that is higher than in the United States. The researchers in this study focused on Brazil, in particular, where an estimated 60,000 new cases of breast cancer were diagnosed in 2018.

The scientists discovered that women with TNBC had specific alterations in copies of their genes that directly influenced the expression of 17 miRNAs compared to women with other forms of breast cancer who did not have these alterations. They also found that the expression levels of the majority of these miRNAs were associated with the tumor’s clinical aggressiveness (advanced grade and stage).

“The panel of miRNAs we identified indicate potential, critical cancer-related pathways and gene networks that could be targeted for the treatment of TNBC in Latinas, once our findings are validated by larger studies,” concluded Cavalli. “Targeting these genetic alterations, that represent the unique biology of their tumors, may lead to more efficient treatments, which could increase the longevity of Latina women who do not have many therapeutic options to fight this very aggressive disease.”

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In addition to Cavalli, authors include: Bruna M. Sugita, Department of Genetics, Federal University of Paraná, Curitiba, PR, Brazil and Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brazil; Silma R. Pereira, Department of Biology, Federal University of Maranhão, São Luis, MA, Brazil; Rodrigo C. de Almeida, Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Mandeep Gill, Akanksha Mahajan, Anju Duttargi, and Saurabh Kirolikar, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Paolo Fadda, Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Rubens S. de Lima and Cicero A. Urban, Breast Unit, Hospital Nossa Senhora das Graças, Curitiba, PR, Brazil; Kepher Makambi, Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center;  Subha Madhavan, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center and Innovation Center for Biomedical Informatics, Lombardi Comprehensive Cancer Center, Georgetown University; Simina M. Boca, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Innovation Center for Biomedical Informatics (ICBI), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Yuriy Gusev, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Innovation Center for Biomedical Informatics (ICBI), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Iglenir J. Cavalli and Enilze M.S.F. Ribeiro, Department of Genetics, Federal University of Paraná, Curitiba, PR, Brazil.

The authors report no relationships or conflicts of interest to disclose relevant to this study. 

This research was supported by the Georgetown University Center of Excellence in Regulatory Science and Innovation (CERSI; U01FD004319) and was partially supported by NIH/NCI grant P30-CA051008.

Sugita1 BM, Pereira SR, et al. Integrated copy number and miRNA expression analysis in triple

negative breast cancer of Latin American patients. Oncotarget. No. 58. Oct. 22, 2019.

About Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington D.C. area. It serves as the research engine for MedStar Health, Georgetown University’s clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, New Jersey. The consortium reflects an integrated cancer research enterprise with scientists and physician-researchers from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is a member of the NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).

About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic health and science center with a four-part mission of research, teaching, service and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.  Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter).

Tipo Agressivo de Câncer de Mama é Influenciado pela Ação Conjunta de Genes e RNA

Mulheres Latinas são frequentemente diagnosticadas em estágios avançados de câncer de mama do tipo triplo-negativo e podem se beneficiar de tratamentos que tem como alvo a biologia de seus tumores

WASHINGTON — Mulheres diagnosticadas com um tipo menos comum e agressivo de câncer de mama, conhecido como triplo-negativo, podem ser diferenciadas de mulheres com outras formas da doença através de um painel de 17 moléculas pequenas de RNA. Estas moléculas podem ser diretamente influenciadas por alterações genéticas encontradas tipicamente em células cancerosas.

Pesquisadores liderados pela Dra. Luciane Cavalli, da Georgetown Lombardi Comprehensive Cancer Center, e colaboradores, descobriram que variações na expressão, se aumentada ou diminuída, dessas moléculas pequenas de RNAs, conhecidos como microRNAs (miRNAs) podem parcialmente explicar as taxas desiguais de câncer de mama do tipo triplo-negativo (TNBC) em mulheres Latinas, quando comparadas a mulheres brancas de origem não-hispânicas e potencialmente resultar em opções de tratamento mais eficazes.

Estes são os resultados de um novo estudo publicado em 22 de outubro de 2019 na revista Oncotarget.

“Devido a variabilidade na expressão de miRNAs de acordo com a raça ou etnia, determinamos que era crítica a caracterização da linhagem genômica (ou ancestralidade) de mulheres com TNBC” afirmou Dra. Cavalli, professora adjunta de Medicina da Georgetown University School of Medicine e professora pesquisadora do Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brasil. “Apesar do foco do nosso estudo ser a genética, permanecemos cientes de que fatores não-genéticos, como as condições socioeconômicas das pacientes, podem impactar significativamente as taxas de incidência do TNBC e outros tipos de câncer de mama”.

Estatísticos estimam que o TNBC ocorre em até um terço das mulheres em países da América Latina, taxa superior ao que ocorre nos Estados Unidos. Os pesquisadores deste estudo se concentraram em pacientes do Brasil, país em que em 2018 foram estimados o diagnóstico de 60.000 novos casos de câncer de mama. 

Os cientistas descobriram que mulheres com TNBC apresentam alterações específicas do número de cópias dos seus genes que influenciam a expressão de 17 miRNAs quando comparadas a mulheres com outras formas de câncer de mama, que não apresentam essas alterações. Eles também observaram que os níveis de expressão da maioria desses miRNAs estavam associados a agressividade clínica do tumor (grau e estágio avançado). 

“O painel de miRNAs que identificamos indica potenciais vias celulares e “networks” de genes críticos ao câncer, que podem ser alvos no desenvolvimento de tratamentos contra TNBC em mulheres Latinas, assim que os nossos dados sejam validados em estudos maiores”, concluiu a Dra. Cavalli. “Utilizando estas alterações genéticas como alvo, que representam a biologia única desses tumores, pode-se desenvolver tratamentos mais eficientes, o que pode aumentar a longevidade de mulheres Latinas que não possuem muitas opções terapêuticas para lutar contra essa doença agressiva”. 

Além da Dra. Luciane Cavalli, autores incluem: Bruna M. Sugita, Departmento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brasil e Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brasil; Silma R. Pereira, Departmento de Biologia, Universidade Federal do Maranhão, São Luis, MA, Brasil; Rodrigo C. de Almeida, Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Mandeep Gill, Akanksha Mahajan, Anju Duttargi, e Saurabh Kirolikar, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Paolo Fadda, Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Rubens S. de Lima and Cicero A. Urban, Unidade da Mama, Hospital Nossa Senhora das Graças, Curitiba, PR, Brazil; Kepher Makambi, Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center;  Subha Madhavan, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center and Innovation Center for Biomedical Informatics, Lombardi Comprehensive Cancer Center, Georgetown University; Simina M. Boca, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Innovation Center for Biomedical Informatics (ICBI), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Yuriy Gusev, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Innovation Center for Biomedical Informatics (ICBI), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Iglenir J. Cavalli and Enilze M.S.F. Ribeiro, Departmento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brasil.

Os autores declaram não haver conflito de interesse relevante a este estudo.

Esta pesquisa foi financiada pelo Georgetown University Center of Excellence in Regulatory Science and Innovation (CERSI; U01FD004319) e foi parcialmente financiada pelo NIH/NCI grant P30-CA051008.

Sugita BM, Pereira SR, et al. Integrated copy number and miRNA expression analysis in triple negative breast cancer of Latin American patients. Oncotarget. No. 58. Oct. 22, 2019. 

Sobre Georgetown Lombardi Comprehensive Cancer Center
Georgetown Lombardi Comprehensive Cancer Center é designado pelo Instituto Nacional do Câncer (National Cancer Institute (NCI)) como um centro compreensivo de câncer. Como parte do Centro Médico Universitário de Georgetown (Georgetown University Medical Center), Georgetown Lombardi é o único centro compreensivo de câncer na área de Washington D.C. Ele funciona como um centro de pesquisa para a MedStar Health, parceira clínica da Georgetown University. Georgetown Lombardi também possui um consórcio reconhecido pelo NCI com o John Theurer Cancer Center/Hackensack Meridian Health no condado de Bergen, New Jersey. O consórcio reflete uma iniciativa de pesquisa integrada em câncer com cientistas e pesquisadores médicos de ambos os centros. Georgetown Lombardi almeja a melhora no diagnóstico, tratamento e prevenção do câncer através de pesquisas básica, translacional e clínica, cuidado com o paciente, educação da população e servindo as comunidades da região de Washington, enquanto o seu membro de consórcio John Theurer Cancer Center/Hackensack Meridian Health serve comunidades na região do norte de New Jersey. Georgetown Lombardi é membro do NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi é financiado em parte pelo National Cancer Institute Cancer Center Support Grant (P30CA051008). Conecte-se com Georgetown Lombardi no Facebook (Facebook.com/GeorgetownLombardi) e Twitter (@LombardiCancer).

Sobre Georgetown University Medical Center
Georgetown University Medical Center (GUMC) é um centro acadêmico de saúde e ciência reconhecido internacionalmente com uma missão de quatro partes: pesquisa, ensino, serviço e cuidado ao paciente (através da MedStar Health). A missão da GUMC é desempenhada com forte ênfase no serviço ao público e com dedicação ao princípio Católico Jesuíta da cura personalis ou “cuidado da pessoa como um todo”. O Medical Center inclui a School of Medicine e a School of Nursing & Health Studies, ambos nacionalmente ranqueados; Georgetown Lombardi Comprehensive Cancer Center, designado como um centro compreensivo de câncer pelo National Cancer Institute; e a Biomedical Graduate Research Organization, responsável pela maior parte das pesquisas financiadas externamente na GUMC incluindo o prêmio Clinical and Translational Science Award do National Institutes of Health.  Conecte-se com o GUMC no Facebook (Facebook.com/GUMCUpdate) e Twitter (@gumedcenter).

 


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