Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

Tharmapalan, Pirashaanthy; Mahendralingam, Mathepan; Berman, Hal K.; Khokha, Rama

doi:10.15252/embj.2018100852

Cited by 83 publications

(80 citation statements)

References 220 publications

(323 reference statements)

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“…That is, genome states that were associated with cancer arise before any detectable cancer exists. In the context of previous transcriptome profiling that showed ER+ luminal-subtype cancers have similar profiles to those of mature luminal cells [Tharmapalan et al, 2019], we speculate that we have identified an epigenetic mechanism to explain why luminal-subtype cancers have higher incidence in older women. That is, genes for key epigenetic regulatory proteins are themselves epigenetically regulated with age, including hypomethylation of CXXC5 at a PPR that is enriched for ESR1 binding motifs.…”

Section: Discussionsupporting

confidence: 50%

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

Sayaman

Miyano

Senapati

et al. 2021

Preprint

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Aging causes molecular changes that manifest as stereotypical phenotypes yet aging-associated diseases progress only in certain individuals. At lineage-specific resolution, we show how stereotyped and variant responses are integrated in mammary epithelia. Age-dependent directional changes in gene expression and DNA methylation (DNAm) occurred almost exclusively in luminal cells and implicated genome organizers SATB1 and CTCF. DNAm changes were robust indicators of aging luminal cells, and were either directly (anti-)correlated with expression changes or served as priming events for subsequent dysregulation, such as demethylation of ESR1-binding regions in DNAm-regulatory CXXC5 in older luminal cells and luminal-subtype cancers. Variance-driven changes in the transcriptome of both luminal and myoepithelial lineages further contributed to age-dependent loss of lineage fidelity. The pathways affected by transcriptomic and DNAm changes during aging are commonly linked with breast cancer, and together with the differential variability found across individuals, influence aging-associated cancer susceptibility in a subtype-specific manner.

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Section: Discussionsupporting

confidence: 50%

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

Sayaman

Miyano

Senapati

et al. 2021

Preprint

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“…The molecular mechanisms governing the differentiation of mammary cells are not well understood, but the process involves bipotent stem cells differentiating into unipotent progenitors, and subsequently to luminal, alveolar or myoepithelial cells. While giving rise to lobuloalveolar epithelial cells, stem and progenitor cells are also considered the cell-of-origin in breast cancer [ 21 ]. It has been suggested that breast cancer mainly originates in these undifferentiated cells within the terminal duct of a lobular unit, which are most vulnerable to carcinogenesis [ 10 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Nonhuman primate model in mammary gland biology and neoplasia research

Dewi

Cline

2021

Lab Anim Res

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Research on breast cancer pathogenesis, prevention and drug development remains an important field as this disease is still one of the leading causes of cancer death worldwide. Nonhuman primates, particularly macaque species, may serve as a highly translational animal model in breast cancer studies due to their similarity with humans in genetics, anatomy, reproductive and endocrine physiology including mammary gland development profile. The use of nonhuman primates in biomedical research, however, requires high ethical standards and an increasing expectation to improve strategies to replace, reduce and refine their use. Here, we discuss some key features of nonhuman primate mammary gland biology relevant to their strengths and limitations as models in studies of breast development and cancer risk.

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“…Numerous signaling pathways involved in healthy development have been implicated in BCa progression. These pathways are often linked to cell proliferation, apoptosis, differentiation, and motility [ 16 ]. Three significant pathways govern mammary gland and BCa stem cell development: (1) estrogen receptor (ER) signaling; (2) HER2 signaling; and (3) canonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients

et al. 2021

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Breast cancer (BCa) ranks first in incidence rate among cancers in Arab females. The association between genetic polymorphisms in tumor suppressor genes and the risk of BCa has been studied in many ethnic populations with conflicting conclusions while Arab females and Saudi Arabian studies are still lacking. We screened a cohort of Saudi BCa patients by NGS using a bespoke gene panel to clarify the genetic landscape of this population, correlating and assessing genetic findings with clinical outcomes. We identified a total of 263 mutations spanning 51 genes, including several frequently mutated. Among the genes analyzed, the highest mutation rates were found in PIK3CA (12.9%), BRCA2 (11.7%), BRCA1 (10.2%), TP53 (6.0%), MSH2 (3.8%), PMS2 (3.8%), BARD1 (3.8%), MLH1 (3.4%), CDH1 (3.0%), RAD50 (3.0%), MSH6 (3.0%), NF1 (2.6%), in addition to others. We identified multiple common recurrent variants and previously reported mutations. We also identified 46 novel variants in 22 genes that were predicted to have a pathogenic effect. Survival analysis according to the four most common mutations (BRCA1, BRCA2, TP53, and PIK3CA) showed reduced survival in BRCA1 and BRCA2-mutant patients compared to total patients. Moreover, BRCA2 was demonstrated as an independent predictor of reduced survival using independent Cox proportional hazard models.We reveal the landscape of the mutations associated with BCa in Saudi women, highlighting the importance of routine genetic sequencing in implementation of precision therapies in KSA.

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Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

Cited by 83 publications

References 220 publications

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

Nonhuman primate model in mammary gland biology and neoplasia research

Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients

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