You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells}
Article:
Abstract:
During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T( MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis–free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.
Introduction:
Breast cancer is a heterogeneous disease in which subtypes predicting differential clinical outcome are recognized based on shared patterns of gene expression and mutation, indicating a shared path to cancer[1]. The most striking subtype distinction in breast cancer is provided by expression of ESR1, the estrogen receptor( ER). This divides breast cancer into two very different diseases, recognizable by more than their response to hormones and antiestrogen therapies. For example, the risk of recurrence remains constant for more than 20 y for ER+ disease, but drops dramatically after 5 y for ER- disease[2, 3]. ER+ cancers are also more insensitive to chemotherapy than those that are ER-[4–6]. The basis for this phenotypic dichotomy probably includes the characteristics of the cancer’s cell of origin, which for the basal ER- and luminal ER+ breast cancer subtypes are thought to be the members of the mammary progenitor cell pool[7]. A key transcriptional determinant of cell fate decisions made by the progenitor cells is the ETS transcription factor ELF5[8], which is first expressed as mammary stem cells differentiate to become progenitor cells, coincident with promoter demethylation[9]. In progenitor cells ELF5 levels fall under hormonal control. The systemic hormones of pregnancy prompt local mammary paracrine signals involving RANKL[10–12] to induce ELF5[13, 14], and force a progenitor cell fate decision that establishes the ER- secretory cell lineage responsible for milk production. An alternative progenitor cells fate, that of an ER+ hormone sensing cell, may result if ELF5 levels remain in check due to the dominance of the estrogen-driven phenotype[15]. In luminal breast cancer cells, a mutual negative-regulatory loop between ER and ELF5 occurs, which is dominated by ER and so keeps ELF5 levels low[16]. Conversely, ER- basal breast cancers are characterized by high ELF5 levels, while the stem-cell–like claudin-low subgroup does not express ELF5[16]. Knockdown of ELF5 levels in luminal breast cancer cells has a small effect on proliferation, but a much greater effect is seen in ER- basal cell lines[16]. Importantly, ELF5 levels rise when MCF7 luminal breast cancer cells acquire antiestrogen resistance, and resistant cells become dependent on ELF5 for their proliferation[16]. Thus, increased ELF5 levels provide an escape pathway from inhibition of proliferation by antiestrogen therapy, facilitating disease progression. Whether ELF5 is involved in other key aspects of disease progression, such as metastasis, is unknown. Like primary tumor formation, the acquisition of the metastatic phenotype involves events that alter both intrinsic cell behavior and the extrinsic responses of the host environment. An example of an intrinsic event is the gain of phenotypic plasticity, which regulates the acquisition of invasive and motile characteristics to cancer cells[17]. ELF5 influences phenotypic plasticity by driving the expression of epithelial characteristics, as shown by the fact that knockout of Elf5 in mice, or knockdown of breast cancer cells, caused the loss of epithelial patterns of gene expression, while forced Elf5 expression caused their gain[16, 18]. An example of an extrinsic event is the interaction of the tumor with the host immune system. For example, in the mouse mammary tumor virus–Polyoma Middle T( MMTV-PyMT) model of breast cancer, knockout of CSF-1 depleted macrophages and delayed the development of lung metastases, while over expression caused the migration of macrophages into the tumor and accelerated metastasis[19, 20]. Another important innate immune cell subset active in metastasis of mammary and breast cancer are myeloid-derived suppressor cells( MDSC)[21]. Their circulating numbers are increased by the presence of a tumor[22, 23]. They invade primary tumors, where they promote angiogenesis, via Matrix Metaloproteinases( MMP) secretion and Vascular Endothelial Growth Factor( VEGF) production[24]. These cells inhibit and kill natural killer cells[25] and T-cytotoxic lymphocytes[26], while promoting the proliferation of the T-regulatory cell population and inhibiting dendritic cell maturation; all mechanisms that allow tumors to evade immune control[27]. In some contexts MDSC can also promote type II macrophage development and macrophage-assisted metastasis. In the MMTV-PyMT model of mammary metastasis, increased TGF beta signaling caused their recruitment to primary tumors. Depletion of their numbers reduced the number of lung metastases while tumor cell co-inoculation with MDSC increased the number of lung metastases[28, 29]. We have used our inducible mouse model of mammary-specific ELF5 expression, in the context of luminal mammary tumors induced by PyMT expression, to investigate the roles played by ELF5 during mammary carcinogenesis and progression to metastatic disease.
Discussion:
We show that induction of ELF5 in the PyMT model leads to an increase in lung metastasis because ELF5 recruits MDSCs to the tumor, which promotes leaky vasculature and causes an increase in lung metastasis. Interestingly this effect swamps the cell autonomous effects of ELF5, which predict a tumor suppressor action. Analysis of human breast tumor data suggests that these processes also operate in ER+ breast cancer, and analysis of survival data shows this is prognostic in Luminal A cancers, with ELF5 expression in the cytoplasm clearly identifying a group of luminal A patients with early disease progression. High cytoplasmic ELF5 expression in luminal patients also correlated with a pro-tumor inflammation characterized by decreased cytotoxic T-CD8 lymphocytes. ELF5 has been proposed by Chakrabati and colleagues as a metastasis suppressor gene for all breast cancers[18], but our studies demonstrate that the luminal A subgroup shows the opposite response. Interestingly, we show that ELF5 produces a number of cell-autonomous phenotypic changes that are consistent with a tumor-suppressor role, such as reduced proliferation, invasion, motility, epithelialization, and colonization in a lung-seeding assay, some features of which have been previously reported by us[16] and by Chakrabati and colleagues[18] using different model systems. Our results point to the dominance of the immune system over cell autonomous characteristics in regulating the metastatic behavior of luminal A primary tumors, and so to the importance of pursuing immunoregulatory therapies for luminal A breast cancer. Given the previously described role of ELF5 in the progression to antiestrogen insensitivity in luminal breast cancer, where ELF5 levels rise[16], our results now show that this escape pathway is likely to lead to metastasis via attraction of the innate immune system. This may represent a normal biological response, as macrophages and neutrophils are attracted to the mammary gland during periods of tissue remodeling, especially during weaning when the mammary alveoli are largely resorbed, returning the gland to a series of branched ducts. We observed enrichment of involution and lactation signatures in our transcriptional data in response to ELF5 in both the mouse model and the TCGA data sets. Higher ELF5 expression may result in the tumor being seen by the host as an involuting mammary gland, and the luminal A subgroup may possess a background phenotype which allows or best expresses this appearance. When we treated our mice with the anti MDSC antibody Ly6G we did not completely ablate metastasis, rather we returned metastasis to control levels. This shows other prometastatic pathways continue to operate. One key pathway demonstrated in the PyMT model is the role of macrophages[41], whose numbers were unaffected by ELF5 expression. Hemorrhagic necrosis and intratumoral hemorrhage is observed in breast cancer[42], where it generates pain due to mastodynia in otherwise painless cancers. Short-term induction of ELF5 in the mouse provides a good representation of this human pathology, where isolated hemorrhagic regions are seen. Longer term induction produces a more severe effect than seen in the clinic. The basis for hemorrhage involves the recruitment of MDSC, as shown by its reduction following suppression of these cells with Ly6G antibody. We speculate that the earlier detection of in situ ELF5 tumors is due to the immune cell infiltration, making them larger than the WT controls, since further monitoring showed that they expanded more slowly. Unlike the primary tumor, our data show that colonies of cells growing in the lungs have found a supportive environment. Transcriptional signatures indicative of cellular stress are lost. Necrotic areas are not present and the hemorrhagic phenotype is lost. Interestingly innate immune system recruitment also appears to be absent in the metastases. These results indicate that ELF5 is a major determinate of the lethal phenotype in luminal A breast cancer. Elf5 expression provides a marker that defines early disease progression in this otherwise slow to progress subtype, and may also define a group that should benefit from future immunomodulatory therapies.
The transcription factor Elf5 defines hormone-insensitive and endocrine-therapy–resistant breast cancer . In this study , we have discovered that ELF5 drives the spread of tumor cells to the lungs . We demonstrate that the underlying mechanism for this metastatic spread is via recruitment of the innate immune system . Interestingly , this effect is able to overcome the other tumor-suppressive effects of ELF5 on cancer cells , such as reduced proliferation , motility , and invasion . This important finding challenges the more conventional view that the most potent determinant of metastatic activity lies within the cancer cell . We clearly demonstrate that the innate immune system strongly influences the metastatic activity of cancer cells despite their cell-intrinsic spread potential . Our previous work demonstrated that in luminal breast cancer , ELF5 is a key determinant of antiestrogen therapy resistance . Here , we show that the metastatic mechanism driven by ELF5 is most important in luminal breast cancer patients , in whom higher ELF5 expression is associated with low presence of cytotoxic T lymphocytes , an immune cell population responsible for tumor rejection . Thus , we now see that ELF5 may be behind the two most important processes that cause luminal breast cancers to progress towards the lethal phenotype; resistance to antiestrogen therapy and the development of metastatic activity . This understanding could pave the way for new therapeutic strategies to be devised and new predictive tests to be developed .