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Cul3 is required for normal development of the mammary gland

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Abstract

Cullin 3 (Cul3) has recently been implicated in a multitude of different processes, including the oxidative stress response, autophagy, tumorigenesis, and differentiation. To investigate the role of Cul3 in mammary gland development, we created a mouse model system using Cre-lox targeting where Cul3 is specifically deleted from the mammary gland. Such MMTV-Cre Cul3Flx/Flx mice examined at 2 and 3 months of age show delays and defects in mammary gland development. Mammary ductal trees from Cul3-deficient mammary glands exhibit delayed forward growth through the mammary fat pad, dilation of the ducts, and abnormal morphology of some of the epithelial structures within the gland. Additionally, terminal end buds are larger and less plentiful in MMTV-Cre Cul3Flx/Flx mammary glands, and there is significantly less primary and secondary branching compared to control animals. In contrast, by 6 months of age, the mammary ductal tree has grown to fill the entire mammary fat pad in glands lacking Cul3. However, distorted epithelial structures and dilated ducts persist. MMTV-Cre Cul3Flx/Flx mothers are able to nourish their litters, but the process of involution is slightly delayed in mammary glands lacking Cul3. Therefore, we conclude that while Cul3 is not essential for mammary gland function, Cul3 is required for the mammary gland to proceed normally through development.

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Availability of data and material

The data that support the findings of this study are available from the corresponding author (JDS), upon request.

Abbreviations

BrdU:

5′-Bromo-2′-deoxyuridine

Cul:

Cullin

ER:

Estrogen receptor

H&E:

Hematoxylin and eosin

IGF1:

Insulin-like growth factor 1

MATH:

Meprin and TRAF homology

MEF:

Mouse embryonic fibroblasts

MMTV:

Mouse mammary tumor virus

Msx2:

Msh homeobox 2

NRF2:

Nuclear factor erythroid 2-related factor 2

PR:

Progesterone receptor

SPOP:

Speckle-type BTB/POZ protein

TEB:

Terminal end bud

TGF-β:

Transforming growth factor beta

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Funding

Research was supported by grants from National Institutes of Health (US)-Grant number RO1GM082940 to Jeffrey D. Singer and from Susan G. Komen-Award number BCTR0503636 to Jeffrey D. Singer.

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Authors and Affiliations

  1. School of Natural Sciences and Mathematics, Stockton University, Galloway, NJ, USA

    Cristina M. Cummings

  2. Department of Biology, Portland State University, Portland, OR, USA

    Jeffrey D. Singer

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  1. Cristina M. Cummings
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JDS conceived the work. CMC collected and analyzed the data. CMC wrote the manuscript, and JDS provided critical revision of the article. Both authors reviewed the final manuscript.

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Correspondence to Jeffrey D. Singer.

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Cummings, C.M., Singer, J.D. Cul3 is required for normal development of the mammary gland. Cell Tissue Res 385, 49–63 (2021). https://doi.org/10.1007/s00441-021-03456-1

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