{"id":393950,"date":"2026-01-07T13:25:08","date_gmt":"2026-01-07T13:25:08","guid":{"rendered":"https:\/\/www.newsbeep.com\/ca\/393950\/"},"modified":"2026-01-07T13:25:08","modified_gmt":"2026-01-07T13:25:08","slug":"replication-stress-inducing-elf3-upregulation-promotes-brca1-deficient-breast-tumorigenesis-in-luminal-progenitors","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/ca\/393950\/","title":{"rendered":"Replication stress-inducing ELF3 upregulation promotes BRCA1-deficient breast tumorigenesis in luminal progenitors"},"content":{"rendered":"

In this study, we revealed that LPs have the trait of higher replication stress, an important factor for their potential to transformation. The difference in LPs from other cell populations in normal mammary tissue has received considerable attention in the field. Research in mouse mammary tissue has revealed that the overall luminal epithelial cell population is enriched in mitotic, cell cycle, and DNA repair-related pathways under estrogen- and progestogen-stimulated conditions relative to the basal and stromal cell populations (Shiah et al., 2015<\/a>). Subsequently, Casey et al., 2018<\/a> found that LPs of mouse mammary tissue are enriched in DNA repair and cell division pathways. A recent preprint from the same group (Kim et al., 2021<\/a>) continued the analysis of mouse tissue sequencing data and found that in LPs, DNA repair and replication pathways are significantly upregulated, indicating that LPs are more capable of DNA damage repair and thus more tolerant to BRCA1 deficiency. Furthermore, Nolan et al., 2016<\/a> found that RANK+ LPs are highly proliferative and prone to DNA damage. These studies did not reveal the reason for LP’s tendency to transform. In our study, we focus on the characteristics of LPs compared to other cell populations, and using sequencing data from normal human mammary tissues (Lim et al., 2009<\/a>), we reveal that the DNA replication pathways and the cellular response to replication stress pathways are significantly upregulated in LPs compared to those in other cell populations. We argue that high levels of replication stress may be the major source of DNA damage in LPs, resulting in DDR gene upregulation in these cells, and the high proliferation feature of LP could be the main reason for the high replication stress.<\/p>\n

Replication stress is a hallmark of cancer, fueling cancer evolution by increasing genomic instability (Macheret and Halazonetis, 2015<\/a>). LPs have inherently higher replication stress levels, and when BRCA1 is deficient, replication stress is further elevated during the transformation from normal LPs to tumor cells, suggesting that replication stress is an important driver of BRCA1-deficient tumorigenesis and the suppression of replication stress could be a new approach for preventive intervention in BRCA1 mutation carriers with the advantages of being less damaging than prophylactic resection. It was reported that haploinsufficiency in breast epithelial cell cultures from BRCA1 heterozygotes could lead to premature failure through replication stress (Sedic et al., 2015<\/a>). Moreover, we found that both replication stress and BRCA1 deficiency itself can induce high expression of ELF3, which also plays an important role in the tendency of LPs to transform with BRCA1 deficiency. First, ELF3 can help suppress excessive genomic instability, which is crucial for cell tolerance and survival with BRCA1 deficiency. We speculate that high ELF3 expression can help LPs maintain moderate levels of genomic instability that allow cells to proliferate and is sufficient to fuel cancer evolution, including subsequent events, such as p53 mutation and BRCA1 loss of heterozygosity (LOH). Second, ELF3 upregulation can boost LP gene transcription, leading to LP dedifferentiation and expansion. Finally, as an EMT promoter in mammary tissue, ELF3 can accelerate the transformation of LPs to malignant cells. Therefore, high levels of replication stress and ELF3 expression are important factors resulting in the high tendency for LPs to transform (Figure 7<\/a>).<\/p>\n

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Replication stress-inducing ELF3 upregulation promotes BRCA1-deficient breast tumorigenesis.<\/p>\n

Luminal progenitor cells (LPs) have higher replication stress levels under normal conditions (left) and thus are more likely to exceed the tumorigenesis threshold under BRCA1 deficiency (right). Replication stress and BRCA1 deficiency result in further ELF3 upregulation (top right). ELF3 can suppress excessive replication stress and help LPs maintain moderate levels of genomic instability, which is tolerable for cells to proliferate and enough to fuel cancer evolution (a). In non-LP mammary cells, which exhibit inherently low replicative stress, the ELF3 upregulation may enable cells to endure the increased replicative stress caused by BRCA1 deficiency without leading to malignancy. However, in LP cells, which naturally experience higher levels of replicative stress, this ELF3-mediated mechanism may increase susceptibility to cancerous transformation. In addition, ELF3 upregulation can boost LP gene transcription, leading to LP dedifferentiation and expansion (b). Finally, as an EMT promoter in the mammary tissue, ELF3 can accelerate the transformation process from LPs to malignant cells (c).<\/p>\n

A key feature of BRCA1-associated tumors is the tissue specificity, the mechanism of which has long been a research focus. The transcriptional regulation functions of BRCA1 are critical for the development and differentiation of normal mammary tissue. LPs with abnormal expansion have been observed in BRCA1 mutation carriers. Several important differentiation pathways, such as WNT, Notch, and Hedgehog, were downregulated in these abnormal LPs (Hu et al., 2021<\/a>), suggesting that BRCA1 deficiency may lead to a differentiation blockade in LPs and, therefore, abnormal expansion. Our RNA-seq data revealed that the transcriptional profile of BRCA1-deficient MCF10A cells has a striking similarity to that of LPs in normal human mammary tissue, and ELF3 might be a core mediating transcription factor. This finding suggests that BRCA1 has a broad regulatory effect on gene expression in normal mammary cells and has specific functions in LPs; thus, its deficiency causes LPs to maintain a dedifferentiated state, leading to abnormal expansion of this cell population, and ELF3 may be a core transcription factor inducing these changes. In addition, our study reveals another layer of the mechanism underlying the tissue specificity of BRCA1-associated tumors\u2014the capability of BRCA1 to regulate ELF3 expression. ELF3 is an epithelial-specific transcription factor, but the functions of ELF3 in different epithelial tissues vary. For example, ELF3 promotes tumor development in breast, prostate, and lung cancers (Chang et al., 1997<\/a>; Longoni et al., 2013<\/a>; Enfield et al., 2019<\/a>), whereas it suppresses tumorigenesis in bladder and oral squamous cancers (Iwai et al., 2008<\/a>; The Cancer Genome Atlas Research Network, 2014<\/a>). In addition, ELF3 itself plays an important role in the development and differentiation of normal mammary tissue; thus, dysregulation of ELF3 may disturb these processes. Therefore, we suggest that replication stress caused by BRCA1 deficiency leads to upregulation of ELF3 expression in LPs, thus promoting the tissue-specific oncogenic functions of ELF3 and breast tumorigenesis.<\/p>\n

This study also has some limitations. First, we used the MCF10A cell line, which is widely used for investigations into normal human mammary epithelial cells with the advantage of being easy to manipulate and modify, and compared to patient-derived cells, unknown genetic backgrounds in addition to BRCA1 mutations are avoided. However, the transcriptional profile and epigenetic characteristics of this cell line are distinct from those of normal human mammary cell populations and LPs (Pellacani et al., 2016<\/a>); thus, there are certain gaps between the cell model and real LP cells. Although our data show that MCF10A cells can reflect the actual functions of BRCA1 in terms of maintaining genomic stability (Figure 1B and C<\/a>) and our RNA-seq data demonstrate enrichment in the known transcriptional target genes of BRCA1, the effect of BRCA1 defects and replication stress in LPs needs to be further verified in primary human mammary cell populations. An analysis of TNBC as well as basal-like tumor data needs to be further confirmed in BRCA1-deficient breast cancer. Second, the higher replication stress levels in LPs may lead to altered expression or modifications of molecules other than ELF3, affecting the development and progression of BRCA1-associated breast cancer, which also needs to be further explored. In addition, there are likely other DEGs in our BRCA1-deficient RNA-seq that play important roles in the progression of BRCA1-associated breast cancer, and these genes also have potential research value.<\/p>\n

Taken together, we revealed that LPs have a trait of higher replication stress, endowing them with the potential for transformation with BRCA1 deficiency. Moreover, the levels of replication stress gradually increase during tumorigenesis, indicating that replication stress is a driving factor of BRCA1-associated malignant transformation. Mechanistically, ELF3 is significantly upregulated upon replication stress and BRCA1 deficiency, which can help suppress excessive genomic instability by stabilizing the DNA replication process, empowering LPs to tolerate and to transform with BRCA1 deficiency. In cells with inherently low replicative stress, such as other non-LP mammary cells, the ELF3-associated mechanism might help cells endure the high replicative stress caused by BRCA1 deficiency without leading to cancerous changes. However, in LP cells, which naturally experience higher replicative stress, this ELF3-related mechanism may make them more susceptible to transformation into cancer cells. Notably, BRCA1 deficiency causes a tendency for cells to display characteristics of the LP transcriptional profile, and ELF3 is a core transcription factor mediating this process. Our study reveals why BRCA1 deficiency is prone to result in tumorigenesis in LPs and elucidates the key role of replication stress and ELF3 during this process and suggests promising targets for BRCA1-associated breast cancers.<\/p>\n","protected":false},"excerpt":{"rendered":"In this study, we revealed that LPs have the trait of higher replication stress, an important factor for…\n","protected":false},"author":2,"featured_media":250045,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6],"tags":[49,48,61],"class_list":["post-393950","post","type-post","status-publish","format-standard","has-post-thumbnail","category-technology","tag-ca","tag-canada","tag-technology"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/393950","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/comments?post=393950"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/posts\/393950\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media\/250045"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/media?parent=393950"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/categories?post=393950"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ca\/wp-json\/wp\/v2\/tags?post=393950"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}