Insight into the heterogeneity of breast cancer through next-generation sequencing

Russnes, Hege G.; Navin, Nicholas E.; Hicks, James; Børresen-Dale, Anne Lise

doi:10.1172/jci57088

Cited by 224 publications

(168 citation statements)

References 105 publications

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“…We analyzed the effect of hypoxia (1% O 2 for 24 h) on the production of MVs by three human breast cancer cell lines: MCF-7 expresses the estrogen and progesterone receptors, but not HER2, and is classified as luminal subtype based on its gene expression pattern, whereas MDA-MB-231 and MDA-MB-435 cells (hereafter designated MDA-231 and MDA-435) do not express estrogen or progesterone receptors or HER2 (i.e., triple negative) and are classified as basallike/claudin-low subtype by gene expression criteria (43,44 (29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang

Gilkes²,

Takano³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

407

370

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Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxiainducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.orthotopic transplantation | triple negative breast cancer | oxygen | tumor microenvironment | mammary fat pad implantation

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Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang

Gilkes²,

Takano³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

407

370

View full text Add to dashboard Cite

show abstract

“…Thus, activating mutations in exons 9 or 20 in the PI3K subunit PIK3CA have been detected in 15-25% of all breast cancers, 156 but are seen more frequently among oestrogen receptor-positive tumours belonging to the luminal A class. 157 In addition, approximately 5% of breast cancers may harbour activating mutations in AKT. 158 The fact that strong immunostaining for Akt has been associated with a poor prognosis in breast cancer patients independent of adjuvant therapy [159][160][161] indicates a general prognostic role for activation of the PI3K/Akt system in breast cancer.…”

Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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“…16 This way it will be possible to effectively assess the overall mutational landscape of tumours in the near future 57 thus increasing our ability to evaluate the degree of intra and inter-tumour heterogeneity of a single patient. 6 In order to ensure the reliability of results achieved through these techniques the Next Generation Sequencing Standardization of Clinical Testing workgroup advocates that all mutations with clinical implications should be corroborated by alternative methods.…”

Section: Future Challengesmentioning

confidence: 99%

Genetic Heterogeneity in Colorectal Cancer and its Clinical Implications

et al. 2015

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RESUMOApesar dos recentes avanços no desenvolvimento de métodos complementares de diagnóstico e de novas terapêuticas dirigidas, o cancro colo-rectal continua a ser uma importante causa mundial de morbilidade e mortalidade. Neste sentido, têm sido desenvolvidos nos últimos anos inúmeros trabalhos de investigação com o intuito de encontrar possíveis marcadores de mau prognóstico ainda não caracterizados. A existência de uma arquitectura tumoral complexa formada por vários subclones com heterogeneidade genética entre si tem sido consistentemente apontada em linhas de investigação recentes como um elemento de particular importância. Esta característica parece ter implicações em factores tão relevantes como a representatividade da amostragem tumoral de biópsias para diagnóstico genético e a eficácia de terapias dirigidas, existindo um crescente grau de evidência da relação entre a heterogeneidade genética e o prognóstico dos doentes. O uso generalizado de técnicas de sequenciação de nova geração irá permitir uma melhor compreensão do verdadeiro grau de heterogeneidade genética dos tumores colo-rectais, das suas causas e do seu real impacto na evolução da doença. Nesta revisão pretendemos analisar as recentes descobertas relacionadas com a heterogeneidade genética do cancro colo-rectal, bem como as suas principais implicações clínicas. Palavras-chave: Heterogeneidade Genética; Investigação Médica Translacional; Neoplasias Colo-Rectais/genética; Terapia Molecular Dirigida. ABSTRACTDespite the recent advances in the development of complementary diagnostic exams and modern targeted therapies, colorectal cancer remains a major cause of morbidity and mortality worldwide. In this context, a lot of research has been conducted in the last years to find new markers of poor prognosis. The existence of a complex tumour architecture formed by multiple subclones genetically heterogeneous has been increasingly considered in recent studies as an element of particular importance. This feature seems to influence factors as relevant as the representativeness of tumour biopsies for genetic diagnosis and the efficacy of targeted therapies. There is growing evidence suggesting a relation between genetic heterogeneity and the patients' prognosis. The widespread use of next-generation sequencing techniques will allow a better understanding of the true degree of genetic heterogeneity in colorectal tumours, its causes and impact on the course of the disease. In this review we intend to analyse the recent findings related to the genetic heterogeneity of colorectal cancer, as well as its major clinical implications.

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Insight into the heterogeneity of breast cancer through next-generation sequencing

Cited by 224 publications

References 105 publications

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Genetic Heterogeneity in Colorectal Cancer and its Clinical Implications

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