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A clinically relevant bi-cellular murine mammary tumor model as a useful tool for evaluating the effect of retinoic acid signaling on tumor progression

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Abstract

Background

The effect of retinoic acid (RA) on breast cancer progression is controversial. Our objective was to obtain information about breast cancer progression, taking advantage of the ER-negative murine mammary adenocarcinoma model LM38 (LM38-LP constituted by luminal (LEP) and myoepithelial-like cells (MEP), LM38-HP mainly composed of spindle-shaped epithelial cells, and LM38-D2 containing only large myoepithelial cells), and to validate the role of the retinoic acid receptors (RARs) in each cell-type compartment.

Materials and methods

We studied the expression and functionality of the RARs in LM38 cell lines. We analyzed cell growth and cell cycle distribution, apoptosis, the activity of proteases, motility properties, and expression of the molecules involved in these pathways. We also evaluated tumor growth and dissemination in vivo under retinoid treatment.

Results

LM38 cell lines expressed most retinoic receptor isotypes that were functional. However, only the bi-cellular LM38-LP cells responded to retinoids by increasing RARβ2 and CRBP1 expression. The growth of LM38 cell sublines was inhibited by retinoids, first by inducing arrest in MEP cells, then apoptosis in LEP cells. Retinoids induced inhibitory effects on motility, invasiveness, and activity of proteolytic enzymes, mainly in the LM38-LP cell line. In in-vivo assays with the LM38-LP cell line, RA treatment impaired both primary tumor growth and lung metastases dissemination.

Conclusion

These in-vivo and in-vitro results show that to achieve maximum effects of RA on tumor progression both the LEP and MEP cell compartments have to be present, suggesting that the interaction between the LEP and MEP cells is crucial to full activation of the RARs.

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Acknowledgments

This work is dedicated to the memory of Dr Rafael Mira y Lopez. It was supported by grants from the Fogarty International Center, NIH (1 R03 TW007207-01), UBACyT (M003, M243 and U404), and FONCyT (PICT 00417 and PICT 01296. Préstamo BID). Confocal laser scanning microscopy was performed at the MSSM-Microscopy Shared Resource Facility, supported by funding from an NIH-NCI shared resources grant (5R24 CA095823-04), an NSF Major Research Instrumentation grant (DBI-9724504), and an NIH shared instrumentation grant (1 S10 RR0 9145-01).

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Authors and Affiliations

  1. Research Area, Institute of Oncology “Angel H. Roffo”, University of Buenos Aires, 5481 San Martín Ave, C1417DTB, Buenos Aires, Argentina

    Laura Beatriz Todaro, María José Veloso, Paola Bernadette Campodónico, Lydia Inés Puricelli & Elisa Dora Bal de Kier Joffé

  2. Division of Hematology-Oncology, Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA

    Eduardo Francisco Farías

  3. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Laura Beatriz Todaro, Paola Bernadette Campodónico, Lydia Inés Puricelli & Elisa Dora Bal de Kier Joffé

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  1. Laura Beatriz Todaro
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  2. María José Veloso
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  3. Paola Bernadette Campodónico
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  4. Lydia Inés Puricelli
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  5. Eduardo Francisco Farías
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  6. Elisa Dora Bal de Kier Joffé
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Corresponding author

Correspondence to Elisa Dora Bal de Kier Joffé.

Additional information

L. B. Todaro, M. J. Veloso contributed equally to this paper.

P. B. Campodónico, CONICET Fellow.

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Todaro, L.B., Veloso, M.J., Campodónico, P.B. et al. A clinically relevant bi-cellular murine mammary tumor model as a useful tool for evaluating the effect of retinoic acid signaling on tumor progression. Breast Cancer 20, 342–356 (2013). https://doi.org/10.1007/s12282-012-0342-5

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