Unfavorable effect of calcitriol and its low-calcemic analogs on metastasis of 4T1 mouse mammary gland cancer

Artur Anisiewicz (1, 2) , Agata Pawlik (1, 2) , Beata Filip-Psurska (1, 2) , Eliza Turlej (1, 2) , Stanislaw Dzimira (3, 4) , Magdalena Milczarek (1, 2) , Katarzyna Gdesz (1, 2) , Diana Papiernik (1, 2) , Joanna Jarosz (1, 2) , Dagmara Klopotowska (1, 2) , Andrzej Kutner (5) , André Mazur (6) , Joanna Wietrzyk (1, 2)

1 Department of Experimental Oncology
2 PAN - Polska Akademia Nauk = Polish Academy of Sciences = Académie polonaise des sciences
3 Faculty of Veterinary Medicine
4 Wroclaw University of Environmental and Life Sciences
5 Department of Pharmacology
6 UNH - Unité de Nutrition Humaine

Low vitamin D status is considered as a risk factor for breast cancer and has prognostic significance. Furthermore, vitamin D deficiency increases after adjuvant cancer therapy, which alters bone metabolism increasing the risk of osteoporosis. It is now postulated that vitamin D supplementation in breast cancer treatment delays the recurrence of cancer thereby extending survival. We evaluated the impact of calcitriol and its low-calcemic analogs, PRI2191 and PRI2205, on the tumor growth, angiogenesis, and metastasis of 4T1 mouse mammary gland cancer. Gene expression analysis related to cancer invasion/metastasis, realtime PCR, ELISA, western blotting, and histochemical studies were performed. In vitro studies were conducted to compare the effects of calcitriol and its analogs on 4T1 and 67NR cell proliferation and expression of selected proteins. Calcitriol and its analogs increased lung metastasis without influencing the growth of primary tumor. The levels of plasma 17beta-estradiol and transforming growth factor beta (TGFbeta) were found to be elevated after treatment. Moreover, the results showed that tumor blood perfusion improved and osteopontin (OPN) levels increased, whereas vascular endothelial growth factor (VEGF) and TGFbeta levels decreased in tumors from treated mice. All the studied treatments resulted in increased collagen content in the tumor tissue in the early step of tumor progression, and calcitriol caused an increase in collagen content in lung tissue. In addition, in vitro proliferation of 4T1 tumor cells was not found to be affected by calcitriol or its analogs in contrast to non-metastatic 67NR cells. Calcitriol and its analogs enhanced the metastatic potential of 4T1 mouse mammary gland cancer by inducing the secretion of OPN probably via host cells. In addition, OPN tumor overexpression prevailed over the decreasing tumor TGFbeta level and blood vessel normalization via tumor VEGF deprivation induced by calcitriol and its analogs. Moreover, the increased plasma TGFbeta and 17beta-estradiol levels contributed to the facilitation of metastatic process

Mots clés: metastasis; calcitriol analog; 4T1 mouse mammary gland cancer; osteopontin; TGFβ; mammary malignant tumor

Mots clés: cancer du sein; vitamine D; calcitriol

Domaines: Cancer; Alimentation et Nutrition; Santé publique et épidémiologie

Artur Anisiewicz, Agata Pawlik, Beata Filip-Psurska, Eliza Turlej, Stanislaw Dzimira, et al.. Unfavorable effect of calcitriol and its low-calcemic analogs on metastasis of 4T1 mouse mammary gland cancer. International Journal of Oncology, 2018, 52 (1), pp.103-1026. ⟨10.3892/ijo.2017.4185⟩. ⟨hal-01644030⟩