SAT-126 Breast Adipose Tissue Extracellular Vesicles from Obese Women Increase Breast Cancer Aggressiveness - a Novel Mechanism for the Obesity-Breast Cancer Link

Abstract Background and Objectives: Breast cancer is among the most common cancer in women with 2.1 million new cases detected each year. Numerous studies have demonstrated a connection between body mass index (BMI) and cancer incidence, with obesity (BMI ≥ 30) being responsible for the development of at least 13 types of cancer, and 15% to 20% of total cancer-related mortality. The effects of extracellular vesicles (EVs) derived from the obese adipose tissue microenvironment on breast cancer have not yet been clearly elucidated. Methods: EVs were obtained from media conditioned with human breast adipose tissue from reduction mammoplasty (n=31). Women were healthy at the time of surgery and had no history of breast cancer. Patient samples were stratified based on their body mass index (BMI), with a BMI < 25 considered healthy and a BMI ≥ 25 considered overweight/obese. Breast adipose tissue-derived EVs (AT-EVs) were characterized (Quantitative Mass Spectrometry) and used to treat human breast cancer cell lines, including the ER+ MCF7 and triple negative breast cancer (TNBC) MDA-MB-231. Effects on cell proliferation and migration in vitro, and on tumor growth in a mouse xenograft model, were examined after long-term education with EVs. RNA sequencing was performed to investigate potential reprogramming induced by AT-EVs. Results: We found a positive correlation between protein amount per AT-EV and BMI. Quantitative proteomics of AT-EVs revealed 46 proteins that were significantly higher and 54 proteins that were significantly lower in specimens from women with a BMI ≥ 25 compared to women with a BMI < 25. AT-EVs from patients with a BMI ≥ 25 induced proliferation of MCF7 cells compared to AT-EVs from patients with a BMI < 25. Obese EVs induced a more aggressive phenotype in MDA-MB-231 cells, increasing their invasiveness in vitro. Obese EVs also increased the growth of MCF7 and MDA-MB-231 cells in vivo. Ingenuity pathway analysis of RNA-Seq data identified significant differences in mTOR signaling and canonical pathways associated with altered mitochondrial function. Conclusion: Our studies identify a novel mechanism to explain the obesity-breast cancer link in older women. Namely, that in obesity, the breast microenvironment produces EVs capable of reprogramming breast cancer cells to grow faster and be more aggressive. Identifying which cargo in breast AT-EV mediates these effects may provide new targets for intervention.

Download Full-text

Estrogens and Glucocorticoids in Mammary Adipose Tissue: Relationships with Body Mass Index and Breast Cancer Features

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz268 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1504-e1516 ◽

Cited By ~ 3

Author(s):

Sofia Laforest ◽

Mélissa Pelletier ◽

Nina Denver ◽

Brigitte Poirier ◽

Sébastien Nguyen ◽

...

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Adipose Tissue ◽

Body Mass ◽

Tumor Size ◽

Breast Tumors ◽

Partial Mastectomy ◽

Negatively Associated ◽

Breast Adipose Tissue ◽

Breast Adipose

Abstract Context Adipose tissue is an important site for extragonadal steroid hormone biosynthesis through the expression and activity of P450 aromatase, 11β-hydroxysteroid dehydrogenase (HSD) 1, and 17β-HSDs. The contribution of steroid hormones produced by adjacent adipose tissue for the progression and survival of breast tumors is unknown. Objective To quantify estrogens (estradiol, estrone) and glucocorticoids (cortisol, cortisone) in breast adipose tissue from both healthy and diseased women and their relationships with adiposity indices and breast cancer prognostic markers. Design and setting Breast adipose tissue was collected at time of surgery. Patients Pre- and postmenopausal women undergoing partial mastectomy for treatment of breast cancer (n = 17) or reduction mammoplasty (n = 6) were studied. Interventions Relative estrogen and glucocorticoid amounts were determined by liquid chromatography tandem mass spectrometry. Results The targeted steroids were reliably detected and quantified in mammary adipose tissues. Women with ER+/PR+ tumor had higher relative estradiol amount than women with ER–/PR– tumor (P < .05). The ratio of estradiol-to-estrone was higher in lean women than in women with a body mass index (BMI) ≥ 25 kg/m2 (P < .05). Mixed-model analyses showed that estradiol, cortisone, and cortisol were negatively associated with tumor size (P < .05). Relationships between glucocorticoids and tumor size remained significant after adjustment for BMI. The cortisol-to-cortisone ratio was negatively associated with tumor stage (P < .05) independently of BMI. Conclusions We reliably quantified estrogens and glucocorticoids in breast adipose tissue from healthy women and women suffering from breast cancer. Our findings suggest that smaller breast tumors are associated with higher relative amounts of estradiol and cortisol in adipose tissue.

Download Full-text

Human breast adipose tissue: characterization of factors that change during tumor progression in human breast cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-017-0494-4 ◽

2017 ◽

Vol 36 (1) ◽

Cited By ~ 28

Author(s):

Sabrina Johanna Fletcher ◽

Paula Alejandra Sacca ◽

Mercedes Pistone-Creydt ◽

Federico Andrés Coló ◽

María Florencia Serra ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Tumor Progression ◽

Human Breast Cancer ◽

Tissue Characterization ◽

Human Breast ◽

Breast Adipose Tissue ◽

Breast Adipose

Download Full-text

Estrogen Receptor mRNA Levels in Breast Adipose Tissue Negatively Correlate with Body Mass Index in Premenopausal Women: A Possible Relationship to Breast Cancer Risk.

Journal of the Society for Gynecologic Investigation ◽

10.1016/1071-5576(96)82543-3 ◽

1996 ◽

Vol 3 (2) ◽

pp. 106A

Author(s):

T PRICE

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Estrogen Receptor ◽

Adipose Tissue ◽

Premenopausal Women ◽

Mrna Levels ◽

Receptor Mrna ◽

Breast Adipose Tissue ◽

Estrogen Receptor Mrna ◽

Breast Adipose

Download Full-text

A Correlation Study of Organochlorine Levels in Serum, Breast Adipose Tissue, and Gluteal Adipose Tissue among Breast Cancer Cases in India

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-04-0356 ◽

2005 ◽

Vol 14 (5) ◽

pp. 1113-1124 ◽

Cited By ~ 45

Author(s):

J. A. Rusiecki

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Correlation Study ◽

Breast Adipose Tissue ◽

Breast Adipose

Download Full-text

Obesity and Breast Cancer: The Role of Crown-Like Structures in Breast Adipose Tissue in Tumor Progression, Prognosis, and Therapy

Journal of Breast Cancer ◽

10.4048/jbc.2020.23.e35 ◽

2020 ◽

Vol 23 (3) ◽

pp. 233 ◽

Cited By ~ 2

Author(s):

Sara Socorro Faria ◽

Luís Henrique Corrêa ◽

Gabriella Simões Heyn ◽

Lívia Pimentel de Sant'Ana ◽

Raquel das Neves Almeida ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Tumor Progression ◽

Breast Adipose Tissue ◽

Breast Adipose

Download Full-text

Low Levels of Omega-3 Long-Chain Polyunsaturated Fatty Acids Are Associated with Bone Metastasis Formation in Premenopausal Women with Breast Cancer: A Retrospective Study

Nutrients ◽

10.3390/nu12123832 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3832

Author(s):

Caroline Goupille ◽

Philippe G. Frank ◽

Flavie Arbion ◽

Marie-Lise Jourdan ◽

Cyrille Guimaraes ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Bone Metastases ◽

Premenopausal Women ◽

Lymph Node Involvement ◽

Axillary Lymph ◽

Breast Adipose Tissue ◽

Breast Adipose ◽

Node Involvement ◽

Low Levels

In the present study, we investigated various biochemical, clinical, and histological factors associated with bone metastases in a large cohort of pre- and postmenopausal women with breast cancer. Two hundred and sixty-one consecutive women with breast cancer were included in this study. Breast adipose tissue specimens were collected during surgery. After having established the fatty acid profile of breast adipose tissue by gas chromatography, we determined whether there were differences associated with the occurrence of bone metastases in these patients. Regarding the clinical and histological criteria, a majority of the patients with bone metastases (around 70%) had tumors with a luminal phenotype and 59% of them showed axillary lymph node involvement. Moreover, we found a negative association between the levels of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in breast adipose tissue and the development of bone metastases in premenopausal women. No significant association was observed in postmenopausal women. In addition to a luminal phenotype and axillary lymph node involvement, low levels of n-3 LC-PUFA in breast adipose tissue may constitute a risk factor that contributes to breast cancer bone metastases formation in premenopausal women.

Download Full-text

The in vitro secretion of human leptin is gender-dependent but independent of the body mass index of the donors

Acta Endocrinologica ◽

10.1530/eje.0.1430711 ◽

2000 ◽

pp. 711-714 ◽

Cited By ~ 14

Author(s):

C Menendez ◽

R Baldelli ◽

M Lage ◽

X Casabiell ◽

V Pinero ◽

...

Keyword(s):

Body Mass Index ◽

Adipose Tissue ◽

Body Mass ◽

Tissue Sample ◽

Secretory Activity ◽

The Body ◽

Secretory Rate ◽

Omental Adipose Tissue

OBJECTIVE: Leptin is an adipocyte-secreted hormone acting as a signal to the central nervous system, where it regulates energy homeostasis and neuroendocrine processes. Leptin plasma levels are mainly regulated by the percentage of body fat, but are also controlled by several metabolic and nutritional variables. Data regarding leptin secretion suggest that it is gender regulated, and higher levels are present in women than men; however, the biological basis for this sex-related difference is unknown. To clarify those points, a systematic study with tissue cultures from human omental adipose tissue was performed. DESIGN AND METHODS: Surgically obtained samples from 137 patients (68 women, 69 men) were evaluated. The assay was standardized in periods of 24 h ending at 96 h. Each adipose tissue sample from a single donor was incubated in triplicate and leptin results expressed as the mean of the integrated secretion into the medium (nanograms of leptin/g tissue per time). RESULTS: Tissue adipose cultures showed a steady leptin secretion throughout the 96 h studied, with the peak of secretory activity reached at 48 h; afterwards, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in the 24 h and 48 h period, as well as the area under the curve analyzed in the 0-48 h period, showed a gender-based difference that was significantly (P<0. 05) higher in women than in men. When data of spontaneous leptin secretion were correlated with the body mass index (BMI) of the donors, no correlation was found. This suggests that in vivo leptin levels are dependent on the total amount of fat of the individual, but independent of the leptin secretory rate by the adipose tissue of the donor. CONCLUSIONS: Leptin secretion from omental adipose tissue in vitro is: (i) significantly higher in samples from women than in samples from men; and (ii) not correlated with the BMI, showing that in vitro leptin secretion is not related to the adiposity of the donor.

Download Full-text

Persistent Organic Pollutants and Breast Cancer: A Systematic Review and Critical Appraisal of the Literature

Cancers ◽

10.3390/cancers11081063 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1063 ◽

Cited By ~ 3

Author(s):

Kaoutar Ennour-Idrissi ◽

Pierre Ayotte ◽

Caroline Diorio

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Adipose Tissue ◽

Organic Pollutants ◽

Persistent Organic Pollutants ◽

Cancer Incidence ◽

Breast Cancer Incidence ◽

Epidemiological Studies ◽

Breast Adipose Tissue ◽

Breast Adipose

Persistent organic pollutants (POPs) bioaccumulate in the food chain and have been detected in human blood and adipose tissue. Experimental studies demonstrated that POPs can cause and promote growth of breast cancer. However, inconsistent results from epidemiological studies do not support a causal relationship between POPs and breast cancer in women. To identify individual POPs that are repeatedly found to be associated with both breast cancer incidence and progression, and to demystify the observed inconsistencies between epidemiological studies, we conducted a systematic review of 95 studies retrieved from three main electronic databases. While no clear pattern of associations between blood POPs and breast cancer incidence could be drawn, POPs measured in breast adipose tissue were more clearly associated with higher breast cancer incidence. POPs were more consistently associated with worse breast cancer prognosis whether measured in blood or breast adipose tissue. In contrast, POPs measured in adipose tissue other than breast were inversely associated with both breast cancer incidence and prognosis. Differences in biological tissues used for POPs measurement and methodological biases explain the discrepancies between studies results. Some individual compounds associated with both breast cancer incidence and progression, deserve further investigation.

Download Full-text