JNK1 stress signaling is hyper-activated in high breast density and the tumor stroma: Connecting fibrosis, inflammation, and stemness for cancer prevention

Lisanti, Michael P.; Tsirigos, Aristotelis; Pavlides, Stephanos; Reeves, Kimberley J.; Peiris-Pagès, Maria; Chadwick, Amy L.; Sánchez‐Alvarez, Rosa; Lamb, Rebecca; Howell, Anthony; Martinez‐Outschoorn, Ubaldo; Sotgia, Federica

doi:10.4161/cc.27379

Cited by 45 publications

(41 citation statements)

References 65 publications

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“…the incorrect activation of the wound healing response), is characteristic of several solid tumors including pancreas and breast [8]. Our finding that PDGFRα activation in mammary fibroblasts induces such desmoplasia in absence of an oncogenic hit provides evidence that quiescent mammary fibroblasts expressing constitutive PDGFRα have the capacity to become fibrosis-associated fibroblasts, whose phenotype more closely resembles cancer-associated fibroblasts (CAFs) [8], [62]. Gene expression profiling of MMFs isolated from the Fsp-cre;Pdgfra ki/+ mice revealed that CAF-associated collagen remodeling genes such as Mmp3 [63] and Loxl1 [11], [64] are significantly up-regulated, suggesting a priming of the tumor microenvironment for oncogenesis.…”

Section: Discussionmentioning

confidence: 83%

Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

et al. 2017

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The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA) and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary gland development, resulting in increased mammary stiffness and increased potential for tumor growth.

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Section: Discussionmentioning

confidence: 83%

Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

et al. 2017

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“…Gene expression profiles of fibroblasts derived from dense and non-dense areas of the breast indicate marked differences in expression. Expression of genes associated with inflammation (such as c-Jun N-terminal kinases, or JNK) and several signaling pathways is upregulated and suggests the use of, for example, JNK inhibitors, already in the clinic for treatment of overt disease [ 162 ],[ 163 ]. Some fibroblasts in dense areas resemble cancer-associated fibroblasts in their signaling pathways and production of extracellular aligned collagen, all potential targets for prevention [ 164 ].…”

Section: The Biology Of Risk and Prevention As An Indicator Of Potentmentioning

confidence: 99%

Risk determination and prevention of breast cancer

et al. 2014

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Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention (tamoxifen, raloxifene, exemestane, and anastrozole) and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0446-2) contains supplementary material, which is available to authorized users.

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“…Lisanti et al [49] isolated fibroblasts from women with high breast density (n=7) and women with low breast density (n=6). They conducted gene-set enrichment analyses and identified gene sets related to high density including stress response, inflammation, stemness, signal transduction, and cancer.…”

Section: Mammographic Density and Breast Tissue Gene Expressionmentioning

confidence: 99%

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

Pettersson

Tamimi

2014

Curr Epidemiol Rep

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Mammographic density is a strong risk factor for breast cancer, independent of other known risk factors. While a number of hypotheses have been proposed, the biological mechanisms underlying the association between mammographic density and breast cancer remain, however, largely unknown. Understanding these mechanisms may help identify opportunities to reduce mammographic density and ultimately breast cancer risk. We review three major areas of research that may help us better understand the biologic underpinnings of mammographic density: heritability and genetics, breast tissue histology and (molecular) pathology, and experimental studies. We summarize the main consistent findings in the literature and identify key areas for future research.

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JNK1 stress signaling is hyper-activated in high breast density and the tumor stroma: Connecting fibrosis, inflammation, and stemness for cancer prevention

Cited by 45 publications

References 65 publications

Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

Stromal PDGFR-α Activation Enhances Matrix Stiffness, Impedes Mammary Ductal Development, and Accelerates Tumor Growth

Risk determination and prevention of breast cancer

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

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