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Long-Chain Omega-3 Polyunsaturated Fatty Acids Modulate Mammary Gland Composition and Inflammation

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Abstract

Studies in rodents have shown that dietary modifications as mammary glands (MG) develop, regulates susceptibility to mammary tumor initiation. However, the effects of dietary PUFA composition on MGs in adult life, remains poorly understood. This study investigated morphological alterations and inflammatory microenvironments in the MGs of adult mice fed isocaloric and isolipidic liquid diets with varying compositions of omega (ω)-6 and long-chain (Lc)-ω3FA that were pair-fed. Despite similar consumption levels of the diets, mice fed the ω-3 diet had significantly lower body-weight gains, and abdominal-fat and mammary fat pad (MFP) weights. Fatty acid analysis showed significantly higher levels of Lc-ω-3FAs in the MFPs of mice on the ω-3 diet, while in the MFPs from the ω-6 group, Lc-ω-3FAs were undetectable. Our study revealed that MGs from ω-3 group had a significantly lower ductal end-point density, branching density, an absence of ductal sprouts, a thinner ductal stroma, fewer proliferating epithelial cells and a lower transcription levels of estrogen receptor 1 and amphiregulin. An analysis of the MFP and abdominal-fat showed significantly smaller adipocytes in the ω-3 group, which was accompanied by lower transcription levels of leptin, IGF1, and IGF1R. Further, MFPs from the ω-3 group had significantly decreased numbers and sizes of crown-like-structures (CLS), F4/80+ macrophages and decreased expression of proinflammatory mediators including Ptgs2, IL6, CCL2, TNFα, NFκB, and IFNγ. Together, these results support dietary Lc-ω-3FA regulation of MG structure and density and adipose tissue inflammation with the potential for dietary Lc-ω-3FA to decrease the risk of mammary gland tumor formation.

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Abbreviations

AA:

Arachidonic acid

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

FA:

Fatty acid

IGF:

Insulin like growth factor

Lc:

Long-chain

MFP:

Mammary fat pad

MG:

Mammary gland

MUFA:

Monounsaturated fatty acid

PUFA:

Polyunsaturated fatty acid

qRT-PCR:

Quantitative real-time polymerase chain reaction

SFA:

Saturated Fatty Acid

SPF:

Specific pathogen free

TEB:

Terminal end bud

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Authors and Affiliations

  1. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Saraswoti Khadge, Geoffrey M. Thiele & James E. Talmadge

  2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Geoffrey M. Thiele, Lynell W. Klassen & James E. Talmadge

  3. Veteran Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    Geoffrey M. Thiele & Lynell W. Klassen

  4. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    John Graham Sharp

  5. Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE, USA

    Timothy R. McGuire

  6. Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA

    Paul N. Black & Concetta C. DiRusso

Authors
  1. Saraswoti Khadge
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  2. Geoffrey M. Thiele
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  3. John Graham Sharp
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  4. Timothy R. McGuire
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  5. Lynell W. Klassen
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  6. Paul N. Black
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  7. Concetta C. DiRusso
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  8. James E. Talmadge
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Correspondence to James E. Talmadge.

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The authors declare that there are no conflicts of interest.

Support

We gratefully acknowledge funding from the Fred & Pamela Buffett Cancer Center’s NIH Cancer Center Support Grant (P30CA036727) for this project. Also, funding from the UNMC College of Medicine (LWK) Endowed Chair.

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Highlights

• Dietary long-chain omega-3 fatty acids (Lc-ω-3FAs) modulate mammary ductal end-point density and branching density in adult mice compared to mice receiving a high ω-6 FA containing diet.

• Dietary Lc-ω-3FAs downregulate the levels of proinflammatory cytokines, adipokines and growth factors and their receptors in association with decreased epithelial cell proliferation as compared to mice maintained on a high omega-6 (ω −6) FA containing diet

• Dietary Lc-ω-3FAs regulate the mammary fat pad (MFP) FA profile and is associated with adipocyte hypertrophy

• Dietary Lc-ω-3FAs decrease MG and abdominal adipose tissue inflammation relative to mice receiving a high ω-6 FA containing diet.

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Khadge, S., Thiele, G.M., Sharp, J.G. et al. Long-Chain Omega-3 Polyunsaturated Fatty Acids Modulate Mammary Gland Composition and Inflammation. J Mammary Gland Biol Neoplasia 23, 43–58 (2018). https://doi.org/10.1007/s10911-018-9391-5

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