Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Campbell, Katie M.; O’Leary, Kathleen A.; Rugowski, Debra E.; Mulligan, William; Barnell, Erica K.; Skidmore, Zachary L.; Krysiak, Kilannin; Griffith, Malachi; Schuler, Linda A.; Griffith, Obi L.

doi:10.1101/442624

Cited by 3 publications

(4 citation statements)

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“…The TC11 cell line was generated from an ER+ mammary tumor that developed in a NRL-PRL female [19]. Like the parent tumors that develop spontaneously as a result of local transgenic prolactin overexpression in the mammary glands [18,20], TC11 cells express low levels of progesterone receptor, but respond to E2 with robust proliferation and changes in gene expression [19]. For some of these studies, 10 000 TC11 cells in 50 μl of sterile PBS were orthotopically injected bilaterally into the caudal mammary fat pads of 10-week-old WT or mCol1a1 FVB/N female mice.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…The paucity of immunocompetent models of ER+ aggressive disease has limited our ability to probe the effects on behavior of primary ER+ tumors and disseminated tumor cells. Here we utilized a hormonally-induced mouse model of ER+ breast cancer, which displays many characteristics of aggressive luminal B clinical cancers [18][19][20]. We used an ER+ cell line derived from these estrogen responsive metastatic cancers , in conjunction with a model of elevated collagen deposition, Col1a1 tm1Jae/+ (mCol1a1) [21], to mimic the desmoplasia surrounding growing tumors.…”

Section: Introductionmentioning

confidence: 99%

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Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer

et al. 2019

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Metastatic, anti-estrogen resistant estrogen receptor α positive (ER+) breast cancer is the leading cause of breast cancer deaths in U.S. women. While studies have demonstrated the importance of the stromal tumor microenvironment in cancer progression and therapeutic responses, effects on the responses of ER+ cancers to estrogen and anti-estrogens are poorly understood, particularly in the complex in vivo environment. In this study, we used an estrogen responsive syngeneic mouse model to interrogate how a COL1A1-enriched fibrotic ECM modulates integrated hormonal responses in cancer progression. We orthotopically transplanted the ER+ TC11 cell line into wildtype (WT) or collagen-dense (Col1a1 tm1Jae/+ , mCol1a1) syngeneic FVB/N female mice. Once tumors were established, recipients were supplemented with 17β-estradiol (E2), tamoxifen, or left untreated. Although the dense/stiff environment in mCol1a1 recipients did not alter the rate of E2induced proliferation of the primary tumor, it fostered the agonist activity of tamoxifen to increase proliferation and AP-1 activity. Manipulation of estrogen activity did not alter the incidence of lung lesions in either WT or mCol1a1 hosts. However, the mCol1a1 environment enabled tamoxifen-stimulated growth of pulmonary metastases and further fueled estrogen-driven growth. Moreover, E2 remodeled peritumoral ECM architecture in WT animals, modifying alignment of collagen fibers and altering synthesis of ECM components associated with increased alignment and stiffness, and increasing FN1 and POSTN expression in the pulmonary metastatic niche. These studies demonstrate dynamic interactions between ECM properties and estrogen activity in progression of ER+ breast cancer, and support the need for therapeutics that target both ER and the tumor microenvironment.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms

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Section: Animals and Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer

et al. 2019

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“…Sequencing data from genetically engineered mouse models is largely lacking, with only a few models having been sequenced [28,[31][32][33]. SNV mutation rates between previous studies and ours indicate similarities, and the small discrepancies may be explained through differences in data processing methods.…”

Section: Discussionmentioning

confidence: 46%

Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

Swiatnicki

Andrechek

2019

Preprint

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The E2F family of transcription factors is important for many cellular processes, from their canonical role in cell cycle regulation to other roles in angiogenesis and metastasis. Alteration of the Rb/E2F pathway occurs in various forms of cancer, including breast cancer. E2F1 ablation has been shown to decrease metastasis in MMTV-Neu and MMTV-PyMT transgenic mouse models of breast cancer. Here we take a bioinformatic approach to determine the E2F1 regulated genomic alterations involved in the metastatic cascade, in both Neu and PyMT models. Through gene expression analysis, we reveal few transcriptome changes in non-metastatic E2F1 -/tumors relative to transgenic tumor controls. However investigation of these models through whole genome sequencing found numerous differences between the models, including differences in the proposed tumor etiology between E2F1 -/and E2F1 +/+ tumors induced by Neu or PyMT.Investigating mutated genes through gene set analysis also found a significant number of genes mutated in the cell adhesion pathway in E2F1 -/tumors, indicating this may be a route for disruption of metastasis in E2F1 -/tumors. Overall, these findings illustrate the complicated nature of uncovering drivers of the metastatic process.

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“…Another study revealed that two small molecule inhibitors, SMI-1 and SMI-6, abrogated PRL-induced HER2 + breast cancer cell invasion and malignant lymphocyte proliferation by binding the extracellular domain of PRLR (63). Moreover, PRL synergizes with canonical WNT signals and KRAS activation to drive the development of ER + mammary tumors, by activating the Notch signaling pathway (64,65). MacDonald et al reported that PRL-inducible EDD E3 ubiquitin ligase promotes TORC1 signaling, anti-apoptotic protein expression, and drug resistance in mammary tumors (66).…”

Section: Research Progress In Prl and Female Prl-related Tumorsmentioning

confidence: 99%

Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review)

Tian

Wang

et al. 2022

Int J Mol Med

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The hypothalamus acts on the pituitary gland after signal integration, thus regulating various physiological functions of the body. The pituitary gland includes the adenohypophysis and neurohypophysis, which differ in structure and function. The hypothalamus-hypophysis axis controls the secretion of adenohypophyseal hormones through the pituitary portal vein system. Thyroid-stimulating hormone, adrenocorticotropic hormone, gonadotropin, growth hormone (GH), and prolactin (PRL) are secreted by the adenohypophysis and regulate the functions of the body in physiological and pathological conditions. The aim of this review was to summarize the functions of female-associated hormones (GH, PRL, luteinizing hormone, and follicle-stimulating hormone) in tumors. Their pathophysiology was described and the mechanisms underlying female hormone-related diseases were investigated. Contents 1. Introduction 2. Growth hormone 3. Prolactin 4. Gonadotropin 5. Conclusions

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Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Cited by 3 publications

References 73 publications

Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer

Dynamic interactions between the extracellular matrix and estrogen activity in progression of ER+ breast cancer

Metastasis is altered through multiple processes regulated by the E2F1 transcription factor

Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review)

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