Conditional expression of Ki-RasG12V in the mammary epithelium of transgenic mice induces estrogen receptor alpha (ERα)-positive adenocarcinoma

Andò, Sebastiano; Malivindi, Rocco; Catalano, Stefania; Rizza, Pietro; Barone, Ines; Panza, Salvatore; Rovito, Daniela; Emprou, C.; Jm, Bornert; Laverny, Gilles; Metzger, Daniel

doi:10.1038/onc.2017.252

Cited by 14 publications

(14 citation statements)

References 51 publications

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“…MDA-MB-231 cells were grown in DMEM:F12 containing 10% FBS. Primary cell line from mouse mammary tumors, mMTC2 was obtained and characterized as described [25]. mMTC2 was cultured in DMEM supplemented with 10% FBS and 1 mg/mL penicillin–streptomycin at 37 °C with 5% CO 2 air.…”

Section: Methodsmentioning

confidence: 99%

Leptin Modulates Exosome Biogenesis in Breast Cancer Cells: An Additional Mechanism in Cell-to-Cell Communication

Giordano

Gelsomino

Barone

et al. 2019

JCM

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Exosomes—small membrane vesicles secreted by both normal and malignant cells upon fusion of endosomal multivesicular bodies (MVBs) with the plasma membrane—play an important role in cell-to-cell communication. During the last decade, several reports have highlighted the involvement of these nanovesicles in many aspects of breast cancer development and progression, but the extracellular signals governing their generation in breast cancer cells have not been completely unraveled. Here, we investigated the role of the obesity hormone leptin, a well-known adipokine implicated in mammary tumorigenesis, on the mechanisms regulating exosome biogenesis and release in both estrogen receptor α (ERα)—positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells. We found that leptin treatment enhanced the number of MVBs in the cytoplasm of breast cancer cells and increased the amount of exosomes released in cell conditioned media. At molecular level, leptin increased the protein expression of Tsg101—a key component of the endosomal sorting complex required for transport I (ESCRT-I)—by a post-transcriptional mechanism involving its direct interaction with the chaperone protein Hsp90. Targeting leptin signaling, by a selective leptin receptor antagonist the peptide LDFI (Leu-Asp-Phe-Ile), abrogated leptin effects on Tsg101 expression and on exosome secretion in breast cancer cells. In conclusion, our findings, identifying for the first time leptin/leptin receptor/Hsp90 axis as an important regulator of exosome generation in mammary carcinoma cells, suggest that targeting this signaling pathway might represent a novel therapeutic strategy to impair exosome secretion and interrupt the dangerous cell-to-cell communication in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Leptin Modulates Exosome Biogenesis in Breast Cancer Cells: An Additional Mechanism in Cell-to-Cell Communication

Giordano

Gelsomino

Barone

et al. 2019

JCM

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“…Cell lines derived from these tumors retain ER and PR and are responsive to E2 in vitro and grow in nude mice as tumor xenografts that are inhibited by the anti-estrogen ICI 182780. This model system however has not been evaluated as yet for whether tumors progress through DCIS or for responsiveness to progesterone [ 97 ].…”

Section: Introductionmentioning

confidence: 99%

The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast

Villanueva

Grimm

Dhamne

et al. 2018

J Mammary Gland Biol Neoplasia

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Ductal carcinoma in situ (DCIS) is a non-obligate precursor to most types of invasive breast cancer (IBC). Although it is estimated only one third of untreated patients with DCIS will progress to IBC, standard of care for treatment is surgery and radiation. This therapeutic approach combined with a lack of reliable biomarker panels to predict DCIS progression is a major clinical problem. DCIS shares the same molecular subtypes as IBC including estrogen receptor (ER) and progesterone receptor (PR) positive luminal subtypes, which encompass the majority (60–70%) of DCIS. Compared to the established roles of ER and PR in luminal IBC, much less is known about the roles and mechanism of action of estrogen (E2) and progesterone (P4) and their cognate receptors in the development and progression of DCIS. This is an underexplored area of research due in part to a paucity of suitable experimental models of ER+/PR + DCIS. This review summarizes information from clinical and observational studies on steroid hormones as breast cancer risk factors and ER and PR as biomarkers in DCIS. Lastly, we discuss emerging experimental models of ER+/PR+ DCIS.

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“…For many years, it was questioned whether mouse models of mammary cancer could be estrogen responsive and model clinical luminal breast cancers. However, the ER+ cancers that develop in the NRL-PRL model, like the Stat1-/-and Kras (G12V) models (Andò et al, 2017;Chan et al, 2012) , demonstrate that the tools available for murine systems can be valuable to study ER+ breast cancer. Even in PRL-induced tumors which have lost dependence on estrogen for growth, ER-mediated signals continue to modulate cell phenotype and cancer stem cell activity (Shea et al, 2018) .…”

Section: Discussionmentioning

confidence: 99%

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

Campbell¹,

O’Leary

Rugowski

et al. 2018

Preprint

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The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole genome and exome sequencing in a discovery cohort (n=5) of end stage tumors revealed canonical activating mutations and copy number amplifications of Kras . The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% (23/29) of tumors. Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors, compared to preneoplastic tissues, in cell-intrinsic processes associated with mitosis, cell adhesion and invasion, as well as in the tumor microenvironment, including immune activity. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors which may model a subset of aggressive clinical ER+ breast cancers.

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Conditional expression of Ki-RasG12V in the mammary epithelium of transgenic mice induces estrogen receptor alpha (ERα)-positive adenocarcinoma

Cited by 14 publications

References 51 publications

Leptin Modulates Exosome Biogenesis in Breast Cancer Cells: An Additional Mechanism in Cell-to-Cell Communication

Leptin Modulates Exosome Biogenesis in Breast Cancer Cells: An Additional Mechanism in Cell-to-Cell Communication

The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast

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

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