Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

Kutasovic, Jamie R.; Reed, Amy E. McCart; Sokolova, Anna; Lakhani, Sunil R.; Simpson, Peter T.

doi:10.3390/cancers12040848

Cited by 15 publications

(11 citation statements)

References 162 publications

(241 reference statements)

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“…Compelling evidence has suggested that intra- and inter-tumoral heterogeneity should be taken into careful consideration for an adequate selection of patients [ 2 , 132 ]. In this respect, liquid biopsy allowing the identification of circulating tumor cells (CTCs) in the peripheral blood and the sequencing of the tumor DNA extracted from CTCs would provide the genetic profile of the malignancy [ 133 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Santolla

Maggiolini

2020

Cancers

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One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Santolla

Maggiolini

2020

Cancers

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“…Breast cancer (BC) is a heterogeneous disease with at least twenty histological subtypes of invasive breast cancer, based on growth patterns and morphology, and three biological subtypes, characterized by the expression of estrogen receptor (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), or the lack of all three receptors (triple-negative BC (TNBC)). The “omics“ technologies have confirmed and further stratified molecular heterogeneity of this disease into biologically and clinically meaningful subtypes, including at least six intrinsic subtypes (normal, claudin-low, luminal A and B, HER2-enriched, and basal) and four TNBC molecular subtypes (basal-like 1 and 2, mesenchymal, and luminal androgen receptor) [ 1 ]. TNBC is among the most aggressive and early metastasizing tumors [ 2 , 3 ], and the poor treatment response and early therapeutic escape from conventional treatments eventually leads to aggressive metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

The Ratio of RAC1B to RAC1 Expression in Breast Cancer Cell Lines as a Determinant of Epithelial/Mesenchymal Differentiation and Migratory Potential

Eiden

Ungefroren

2021

Cells

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Breast cancer (BC) is a heterogenous disease encompassing tumors with different histomorphological phenotypes and transcriptionally defined subtypes. However, the non-mutational/epigenetic alterations that are associated with or causally involved in phenotype diversity or conversion remain to be elucidated. Data from the pancreatic cancer model have shown that the small GTPase RAC1 and its alternatively spliced isoform, RAC1B, antagonistically control epithelial–mesenchymal transition and cell motility induced by transforming growth factor β. Using a battery of established BC cell lines with either a well-differentiated epithelial or poorly differentiated mesenchymal phenotype, we observed subtype-specific protein expression of RAC1B and RAC1. While epithelial BC lines were RAC1Bhigh and RAC1low, mesenchymal lines exhibited the reverse expression pattern. High RAC1B and/or low RAC1 abundance also correlated closely with a poor invasion potential, and vice versa, as revealed by measuring random cell migration (chemokinesis), the preferred mode of cellular movement in cells that have undergone mesenchymal transdifferentiation. We propose that a high RAC1B:RAC1 ratio in BC cells is predictive of an epithelial phenotype, while low RAC1B along with high RAC1 is a distinguishing feature of the mesenchymal state. The combined quantitative assessment of RAC1B and RAC1 in tumor biopsies of BC patients may represent a novel diagnostic tool for probing molecular subtype and eventually predict malignant potential of breast tumors.

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“…The most frequent mutated genes in ERα-positive breast cancers are PIK3CA, GATA3, MAP3K1, KMT2C and TP53. Mutation of CDH1 (encoding E-cadherin) or loss of alleles are common in the lobular subtype (reviewed in [15,255]). In contrast, ESR1 mutations are rare (less < 1%) in primary ERα-positive breast cancers [256] but between 20 and 40% of ESR1 mutations are observed in metastatic breast cancer and influence response to hormone therapy (reviewed in [256][257][258][259][260]).…”

Section: Mutations Of Esr1 In Human Breast Tumorsmentioning

confidence: 99%

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

Rusidzé

Adlanmérini

Chantalat

et al. 2021

Cell. Mol. Life Sci.

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Abstract17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.

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Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

Cited by 15 publications

References 162 publications

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

The Ratio of RAC1B to RAC1 Expression in Breast Cancer Cell Lines as a Determinant of Epithelial/Mesenchymal Differentiation and Migratory Potential

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

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