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

Anisiewicz,Artur; Pawlik,Agata; Filip-Psurska,Beata; Turlej,Eliza; Dzimira,Stanisław; Milczarek,Magdalena; Gdesz,Katarzyna; Papiernik,Diana; Jarosz,Joanna; Kłopotowska,Dagmara; Kutner,Andrzej; Mazur,Andrzej; Wietrzyk,Joanna

doi:10.3892/ijo.2017.4185

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

Authors:
- Artur Anisiewicz
- Agata Pawlik
- Beata Filip-Psurska
- Eliza Turlej
- Stanisław Dzimira
- Magdalena Milczarek
- Katarzyna Gdesz
- Diana Papiernik
- Joanna Jarosz
- Dagmara Kłopotowska
- Andrzej Kutner
- Andrzej Mazur
- Joanna Wietrzyk
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Affiliations: Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53‑114 Wroclaw, Poland, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, 50-375 Wroclaw, Poland, Department of Pharmacology, Pharmaceutical Research Institute, 01-793 Warsaw, Poland, Université Clermont Auvergne, INRA, UNH, F-63000 Clermont-Ferrand, France
Published online on: November 2, 2017 https://doi.org/10.3892/ijo.2017.4185
Pages: 103-126
Copyright: © Anisiewicz et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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, PRI‑2191 and PRI‑2205, on the tumor growth, angiogenesis, and metastasis of 4T1 mouse mammary gland cancer. Gene expression analysis related to cancer invasion/metastasis, real‑time 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 17β-estradiol and transforming growth factor β (TGFβ) 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 TGFβ 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 TGFβ level and blood vessel normalization via tumor VEGF deprivation induced by calcitriol and its analogs. Moreover, the increased plasma TGFβ and 17β-estradiol levels contributed to the facilitation of metastatic process.

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1	Cossetti RJD, Tyldesley SK, Speers CH, Zheng Y and Gelmon KA: Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008. J Clin Oncol. 33:65–73. 2015. View Article : Google Scholar
2	Riemsma R, Forbes CA, Kessels A, Lykopoulos K, Amonkar MM, Rea DW and Kleijnen J: Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. Breast Cancer Res Treat. 123:9–24. 2010. View Article : Google Scholar : PubMed/NCBI
3	Dutta U and Pant K: Aromatase inhibitors: Past, present and future in breast cancer therapy. Med Oncol. 25:113–124. 2008. View Article : Google Scholar
4	Brown SA and Guise TA: Cancer treatment-related bone disease. Crit Rev Eukaryot Gene Expr. 19:47–60. 2009. View Article : Google Scholar : PubMed/NCBI
5	Datta M and Schwartz GG: Calcium and Vitamin D supplementation and loss of bone mineral density in women undergoing breast cancer therapy. Crit Rev Oncol Hematol. 88:613–624. 2013. View Article : Google Scholar : PubMed/NCBI
6	Rizzoli R, Body JJ, Brandi ML, Cannata-Andia J, Chappard D, El Maghraoui A, Glüer CC, Kendler D, Napoli N, Papaioannou A, et al International Osteoporosis Foundation Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease: Cancer-associated bone disease. Osteoporos Int. 24:2929–2953. 2013. View Article : Google Scholar : PubMed/NCBI
7	Coleman R, Body JJ, Aapro M and Hadji P: Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 25(Suppl 3): iii124–iii137. 2014. View Article : Google Scholar : PubMed/NCBI
8	Coleman RE, Rathbone E and Brown JE: Management of cancer treatment-induced bone loss. Nat Rev Rheumatol. 9:365–374. 2013. View Article : Google Scholar : PubMed/NCBI
9	Cepa M and Vaz C: Management of bone loss in postmenopausal breast cancer patients treated with aromatase inhibitors. Acta Reumatol Port. 40:323–330. 2015.
10	Hant FN and Bolster MB: Drugs that may harm bone: Mitigating the risk. Cleve Clin J Med. 83:281–288. 2016. View Article : Google Scholar : PubMed/NCBI
11	Brant J: Vitamin D in the prevention of aromatase inhibitor-induced musculoskeletal symptoms: Is it ready for practice? J Adv Pract Oncol. 3:245–248. 2012.PubMed/NCBI
12	Jacobs ET, Kohler LN, Kunihiro AG and Jurutka PW: Vitamin D and colorectal, breast, and prostate cancers: A review of the epidemiological evidence. J Cancer. 7:232–240. 2016. View Article : Google Scholar : PubMed/NCBI
13	Feldman D, Krishnan AV, Swami S, Giovannucci E and Feldman BJ: The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 14:342–357. 2014. View Article : Google Scholar : PubMed/NCBI
14	Jacot W, Pouderoux S, Thezenas S, Chapelle A, Bleuse JP, Romieu G and Lamy PJ: Increased prevalence of vitamin D insufficiency in patients with breast cancer after neoadjuvant chemotherapy. Breast Cancer Res Treat. 134:709–717. 2012. View Article : Google Scholar : PubMed/NCBI
15	Singer O, Cigler T, Moore AB, Levine AB, Do HT and Mandl LA: Hypovitaminosis D is a predictor of aromatase inhibitor musculoskeletal symptoms. Breast J. 20:174–179. 2014. View Article : Google Scholar : PubMed/NCBI
16	LaPorta E and Welsh J: Modeling vitamin D actions in triple negative/basal-like breast cancer. J Steroid Biochem Mol Biol. 144A:65–73. 2014. View Article : Google Scholar
17	Peppone LJ, Rickles AS, Janelsins MC, Insalaco MR and Skinner KA: The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol. 19:2590–2599. 2012. View Article : Google Scholar : PubMed/NCBI
18	Ness RA, Miller DD and Li W: The role of vitamin D in cancer prevention. Chin J Nat Med. 13:481–497. 2015.PubMed/NCBI
19	Horst R, Prapong S, Reinhardt T, Koszewski N, Knutson J and Bishop C: Comparison of the relative effects of 1,24-dihydroxyvitamin D(2) [1,24-(OH)(2)D(2)], 1,24-dihydroxyvitamin D(3) [1,24-(OH)(2)D(3)], and 1,25-dihydroxyvitamin D(3) [1,25-(OH) (2)D(3)] on selected vitamin D-regulated events in the rat. Biochem Pharmacol. 60:701–708. 2000. View Article : Google Scholar : PubMed/NCBI
20	Wietrzyk J, Pełczyńska M, Madej J, Dzimira S, Kuśnierczyk H, Kutner A, Szelejewski W and Opolski A: Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191). Steroids. 69:629–635. 2004. View Article : Google Scholar : PubMed/NCBI
21	Milczarek M, Filip-Psurska B, Swiętnicki W, Kutner A and Wietrzyk J: Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncol Rep. 32:491–504. 2014. View Article : Google Scholar : PubMed/NCBI
22	Wietrzyk J, Chodyński M, Fitak H, Wojdat E, Kutner A and Opolski A: Antitumor properties of diastereomeric and geometric analogs of vitamin D3. Anticancer Drugs. 18:447–457. 2007. View Article : Google Scholar : PubMed/NCBI
23	Milczarek M, Chodyński M, Filip-Psurska B, Martowicz A, Krupa M, Krajewski K, Kutner A and Wietrzyk J: Synthesis and biological activity of diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, against human HL-60 leukemia and MCF-7 breast cancer cells. Cancers (Basel). 5:1355–1378. 2013. View Article : Google Scholar
24	Filip B, Milczarek M, Wietrzyk J, Chodyński M and Kutner A: Antitumor properties of (5e,7e) analogs of vitamin D3. J Steroid Biochem Mol Biol. 121:399–402. 2010. View Article : Google Scholar : PubMed/NCBI
25	Hisatake J, Kubota T, Hisatake Y, Uskokovic M, Tomoyasu S and Koeffler HP: 5,6-trans-16-ene-vitamin D3: A new class of potent inhibitors of proliferation of prostate, breast, and myeloid leukemic cells. Cancer Res. 59:4023–4029. 1999.PubMed/NCBI
26	Opolski A, Wietrzyk J, Siwinska A, Marcinkowska E, Chrobak A, Radzikowski C and Kutner A: Biological activity in vitro of side-chain modified analogues of calcitriol. Curr Pharm Des. 6:755–765. 2000. View Article : Google Scholar : PubMed/NCBI
27	Wietrzyk J, Nevozhay D, Filip B, Milczarek M and Kutner A: The antitumor effect of lowered doses of cytostatics combined with new analogs of vitamin D in mice. Anticancer Res. 27A:3387–3398. 2007.
28	Wietrzyk J, Milczarek M and Kutner A: The effect of combined treatment on head and neck human cancer cell lines with novel analogs of calcitriol and cytostatics. Oncol Res. 16:517–525. 2007. View Article : Google Scholar
29	Wietrzyk J, Nevozhay D, Milczarek M, Filip B and Kutner A: Toxicity and antitumor activity of the vitamin D analogs PRI-1906 and PRI-1907 in combined treatment with cyclophosphamide in a mouse mammary cancer model. Cancer Chemother Pharmacol. 62:787–797. 2008. View Article : Google Scholar : PubMed/NCBI
30	Milczarek M, Psurski M, Kutner A and Wietrzyk J: Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model. BMC Cancer. 13:2942013. View Article : Google Scholar : PubMed/NCBI
31	Maj E, Filip-Psurska B, Świtalska M, Kutner A and Wietrzyk J: Vitamin D analogs potentiate the antitumor effect of imatinib mesylate in a human A549 lung tumor model. Int J Mol Sci. 16:27191–27207. 2015. View Article : Google Scholar : PubMed/NCBI
32	Blazejczyk A, Papiernik D, Porshneva K, Sadowska J and Wietrzyk J: Endothelium and cancer metastasis: Perspectives for antimetastatic therapy. Pharmacol Rep. 67:711–718. 2015. View Article : Google Scholar : PubMed/NCBI
33	Chodyński M, Wietrzyk J, Marcinkowska E, Opolski A, Szelejewski W and Kutner A: Synthesis and antiproliferative activity of side-chain unsaturated and homologated analogs of 1,25-dihydroxyvitamin D(2). (24E)-(1s)-24-Dehydro-24a-homo-1,25-dihydroxyergocalciferol and congeners. Steroids. 67:789–798. 2002. View Article : Google Scholar
34	DuPré SA, Redelman D and Hunter KW Jr: The mouse mammary carcinoma 4T1: Characterization of the cellular landscape of primary tumours and metastatic tumour foci. Int J Exp Pathol. 88:351–360. 2007. View Article : Google Scholar : PubMed/NCBI
35	Nevozhay D: Cheburator software for automatically calculating drug inhibitory concentrations from in vitro screening assays. PLoS One. 9:e1061862014. View Article : Google Scholar : PubMed/NCBI
36	Wenzel J, Zeisig R and Fichtner I: Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions. Clin Exp Metastasis. 27:25–34. 2010. View Article : Google Scholar
37	DuPre' SA and Hunter KW Jr: Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors. Exp Mol Pathol. 82:12–24. 2007. View Article : Google Scholar
38	Banka CL, Lund CV, Nguyen MTN, Pakchoian AJ, Mueller BM and Eliceiri BP: Estrogen induces lung metastasis through a host compartment-specific response. Cancer Res. 66:3667–3672. 2006. View Article : Google Scholar : PubMed/NCBI
39	MacRitchie AN, Jun SS, Chen Z, German Z, Yuhanna IS, Sherman TS and Shaul PW: Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res. 81:355–362. 1997. View Article : Google Scholar : PubMed/NCBI
40	Yang X, Belosay A, Du M, Fan TM, Turner RT, Iwaniec UT and Helferich WG: Estradiol increases ER-negative breast cancer metastasis in an experimental model. Clin Exp Metastasis. 30:711–721. 2013. View Article : Google Scholar : PubMed/NCBI
41	Garcia CM de S, de Araújo MR, Lopes MTP, Ferreira MAND and Cassali GD: Morphological and immunophenotipical characterization of murine mammary carcinoma 4t1. Braz J Vet Pathol. 7:158–165. 2014.
42	Mi Z, Guo H, Wai PY, Gao C, Wei J and Kuo PC: Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior. J Biol Chem. 279:46659–46667. 2004. View Article : Google Scholar : PubMed/NCBI
43	Sangaletti S, Tripodo C, Sandri S, Torselli I, Vitali C, Ratti C, Botti L, Burocchi A, Porcasi R, Tomirotti A, et al: Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res. 74:4706–4719. 2014. View Article : Google Scholar : PubMed/NCBI
44	Pang H, Lu H, Song H, Meng Q, Zhao Y, Liu N, Lan F, Liu Y, Yan S, Dong X, et al: Prognostic values of osteopontin-c, E-cadherin and β-catenin in breast cancer. Cancer Epidemiol. 37:985–992. 2013. View Article : Google Scholar : PubMed/NCBI
45	Chang P-L, Harkins L, Hsieh Y-H, Hicks P, Sappayatosok K, Yodsanga S, Swasdison S, Chambers AF, Elmets CA and Ho KJ: Osteopontin expression in normal skin and non-melanoma skin tumors. J Histochem Cytochem. 56:57–66. 2008. View Article : Google Scholar
46	Yin M, Soikkeli J, Jahkola T, Virolainen S, Saksela O and Hölttä E: Osteopontin promotes the invasive growth of melanoma cells by activating integrin αvβ3 and down-regulating tetraspanin CD9. Am J Pathol. 184:842–858. 2014. View Article : Google Scholar : PubMed/NCBI
47	Sulpice L, Rayar M, Desille M, Turlin B, Fautrel A, Boucher E, Llamas-Gutierrez F, Meunier B, Boudjema K, Clément B, et al: Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. Hepatology. 58:1992–2000. 2013. View Article : Google Scholar : PubMed/NCBI
48	Pang H, Cai L, Yang Y, Chen X, Sui G and Zhao C: Knockdown of osteopontin chemosensitizes MDA-MB-231 cells to cyclophosphamide by enhancing apoptosis through activating p38 MAPK pathway. Cancer Biother Radiopharm. 26:165–173. 2011. View Article : Google Scholar : PubMed/NCBI
49	Denhardt DT, Noda M, O'Regan AW, Pavlin D and Berman JS: Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 107:1055–1061. 2001. View Article : Google Scholar : PubMed/NCBI
50	Kon S, Nakayama Y, Matsumoto N, Ito K, Kanayama M, Kimura C, Kouro H, Ashitomi D, Matsuda T and Uede T: A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type II collagen antibody-induced arthritis. PLoS One. 9:e1162102014. View Article : Google Scholar
51	Barry ST, Ludbrook SB, Murrison E and Horgan CM: A regulated interaction between alpha5beta1 integrin and osteopontin. Biochem Biophys Res Commun. 267:764–769. 2000. View Article : Google Scholar : PubMed/NCBI
52	Helluin O, Chan C, Vilaire G, Mousa S, DeGrado WF and Bennett JS: The activation state of alphavbeta 3 regulates platelet and lymphocyte adhesion to intact and thrombin-cleaved osteopontin. J Biol Chem. 275:18337–18343. 2000. View Article : Google Scholar : PubMed/NCBI
53	Kale S, Raja R, Thorat D, Soundararajan G, Patil TV and Kundu GC: Osteopontin signaling upregulates cyclooxy-genase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via α9β1 integrin. Oncogene. 33:2295–2306. 2014. View Article : Google Scholar
54	Raja R, Kale S, Thorat D, Soundararajan G, Lohite K, Mane A, Karnik S and Kundu GC: Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis. Oncogene. 33:2053–2064. 2014. View Article : Google Scholar
55	Noda M, Vogel RL, Craig AM, Prahl J, DeLuca HF and Denhardt DT: Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. Proc Natl Acad Sci USA. 87:9995–9999. 1990. View Article : Google Scholar : PubMed/NCBI
56	Xu H, McCann M, Zhang Z, Posner GH, Bingham V, El-Tanani M and Campbell FC: Vitamin D receptor modulates the neoplastic phenotype through antagonistic growth regulatory signals. Mol Carcinog. 48:758–772. 2009. View Article : Google Scholar : PubMed/NCBI
57	Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, Moe OW and Giachelli CM: Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 82:1261–1270. 2012. View Article : Google Scholar : PubMed/NCBI
58	Hu B, Zhou H, Gao H, Liu Y, Yan T, Zou L and Chen L: IFN-γ inhibits osteopontin expression in human decidual stromal cells and can be attenuated by 1α,25-dihydroxyvitamin D3. Am J Reprod Immunol. 68:353–361. 2012. View Article : Google Scholar : PubMed/NCBI
59	Chang PL, Ridall AL and Prince CW: Calcitriol regulation of osteopontin expression in mouse epidermal cells. Endocrinology. 135:863–869. 1994. View Article : Google Scholar : PubMed/NCBI
60	Chang PL and Prince CW: 1α,25-dihydroxyvitamin D3 stimulates synthesis and secretion of nonphosphorylated osteopontin (secreted phosphoprotein 1) in mouse JB6 epidermal cells. Cancer Res. 51:2144–2150. 1991.PubMed/NCBI
61	Blomberg Jensen M, Jørgensen A, Nielsen JE, Steinmeyer A, Leffers H, Juul A and Rajpert-De Meyts E: Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo. Neoplasia. 14:952–963. 2012. View Article : Google Scholar : PubMed/NCBI
62	Chakraborty G, Jain S and Kundu GC: Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res. 68:152–161. 2008. View Article : Google Scholar : PubMed/NCBI
63	Das S, Samant RS and Shevde LA: Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to smoothened-targeting Hedgehog inhibition. J Biol Chem. 288:11824–11833. 2013. View Article : Google Scholar : PubMed/NCBI
64	Shevde LA and Samant RS: Role of osteopontin in the pathophysiology of cancer. Matrix Biol. 37:131–141. 2014. View Article : Google Scholar : PubMed/NCBI
65	Johnstone CN, Smith YE, Cao Y, Burrows AD, Cross RS, Ling X, Redvers RP, Doherty JP, Eckhardt BL, Natoli AL, et al: Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer. Dis Model Mech. 8:237–251. 2015. View Article : Google Scholar : PubMed/NCBI
66	Yu Y, Xiao C-H, Tan L-D, Wang Q-S, Li X-Q and Feng Y-M: Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br J Cancer. 110:724–732. 2014. View Article : Google Scholar
67	Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, et al: Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 165:35–52. 2004. View Article : Google Scholar : PubMed/NCBI
68	Maj E, Papiernik D and Wietrzyk J: Antiangiogenic cancer treatment: The great discovery and greater complexity (Review). Int J Oncol. 49:1773–1784. 2016.PubMed/NCBI
69	Molin DGM, van den Akker NM and Post MJ: Affirmative action of osteopontin on endothelial progenitors. Arterioscler Thromb Vasc Biol. 28:2099–2100. 2008. View Article : Google Scholar : PubMed/NCBI
70	Leen LLS, Filipe C, Billon A, Garmy-Susini B, Jalvy S, Robbesyn F, Daret D, Allières C, Rittling SR, Werner N, et al: Estrogen-stimulated endothelial repair requires osteopontin. Arterioscler Thromb Vasc Biol. 28:2131–2136. 2008. View Article : Google Scholar : PubMed/NCBI
71	Pepper MS: Transforming growth factor-beta: Vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 8:21–43. 1997. View Article : Google Scholar : PubMed/NCBI
72	Costanza B, Umelo IA, Bellier J, Castronovo V and Turtoi A: Stromal modulators of TGF-β in cancer. J Clin Med. 6:72017. View Article : Google Scholar
73	Nakagawa T, Li JH, Garcia G, Mu W, Piek E, Böttinger EP, Chen Y, Zhu HJ, Kang DH, Schreiner GF, et al: TGF-β induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways. Kidney Int. 66:605–613. 2004. View Article : Google Scholar : PubMed/NCBI
74	Orlova VV, Liu Z, Goumans M-J and ten Dijke P: Controlling angiogenesis by two unique TGF-β type I receptor signaling pathways. Histol Histopathol. 26:1219–1230. 2011.PubMed/NCBI
75	Goumans M-J, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P and ten Dijke P: Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 21:1743–1753. 2002. View Article : Google Scholar : PubMed/NCBI
76	Khan Z and Marshall JF: The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res. 365:657–673. 2016. View Article : Google Scholar : PubMed/NCBI
77	Takai K, Le A, Weaver VM and Werb Z: Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget. 7:82889–82901. 2016.PubMed/NCBI
78	Sharon Y, Raz Y, Cohen N, Ben-Shmuel A, Schwartz H, Geiger T and Erez N: Tumor-derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer. Cancer Res. 75:963–973. 2015. View Article : Google Scholar : PubMed/NCBI
79	Weber CE, Kothari AN, Wai PY, Li NY, Driver J, Zapf MA, Franzen CA, Gupta GN, Osipo C, Zlobin A, et al: Osteopontin mediates an MzF1-TGF-β1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene. 34:4821–4833. 2015. View Article : Google Scholar
80	Koli K and Keski-Oja J: 1,25-Dihydroxyvitamin D3 enhances the expression of transforming growth factor beta 1 and its latent form binding protein in cultured breast carcinoma cells. Cancer Res. 55:1540–1546. 1995.PubMed/NCBI
81	Shany S, Sigal-Batikoff I and Lamprecht S: Vitamin D and myofibroblasts in fibrosis and cancer: At cross-purposes with TGF-β/SMAD signaling. Anticancer Res. 36:6225–6234. 2016. View Article : Google Scholar : PubMed/NCBI
82	Tao Q, Wang B, Zheng Y, Jiang X, Pan Z and Ren J: Vitamin D prevents the intestinal fibrosis via induction of vitamin D receptor and inhibition of transforming growth factor-beta1/Smad3 pathway. Dig Dis Sci. 60:868–875. 2015. View Article : Google Scholar
83	Ivanović V, Demajo M, Krtolica K, Krajnović M, Konstantinović M, Baltić V, Prtenjak G, Stojiljković B, Breberina M, Nesković-Konstantinović Z, et al: Elevated plasma TGF-β1 levels correlate with decreased survival of metastatic breast cancer patients. Clin Chim Acta. 371:191–193. 2006. View Article : Google Scholar
84	Moo-Young TA, Larson JW, Belt BA, Tan MC, Hawkins WG, Eberlein TJ, Goedegebuure PS and Linehan DC: Tumor-derived TGF-beta mediates conversion of CD4⁺Foxp3⁺ regulatory T cells in a murine model of pancreas cancer. J Immunother. 32:12–21. 2009. View Article : Google Scholar : PubMed/NCBI
85	Gong D, Shi W, Yi SJ, Chen H, Groffen J and Heisterkamp N: TGFβ signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol. 13:312012. View Article : Google Scholar
86	Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS and Albelda SM: Polarization of tumor-associated neutrophil phenotype by TGF-beta: 'N1' versus 'N2' TAN. Cancer Cell. 16:183–194. 2009. View Article : Google Scholar : PubMed/NCBI
87	Wculek SK and Malanchi I: Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature. 528:413–417. 2015. View Article : Google Scholar : PubMed/NCBI
88	Cho HJ, Jung JI, Lim DY, Kwon GT, Her S, Park JH and Park JHY: Bone marrow-derived, alternatively activated macrophages enhance solid tumor growth and lung metastasis of mammary carcinoma cells in a Balb/C mouse orthotopic model. Breast Cancer Res. 14:R812012. View Article : Google Scholar : PubMed/NCBI
89	Adams LS and Teegarden D: 1,25-dihydroxycholecalciferol inhibits apoptosis in C3H10T1/2 murine fibroblast cells through activation of nuclear factor kappaB. J Nutr. 134:2948–2952. 2004.PubMed/NCBI
90	Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C and Douvdevani A: Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant. 21:889–897. 2006. View Article : Google Scholar : PubMed/NCBI
91	Williams JD, Aggarwal A, Swami S, Krishnan AV, Ji L, Albertelli MA and Feldman BJ: Tumor autonomous effects of Vitamin D deficiency promote breast cancer metastasis. Endocrinology. 157:1341–1347. 2016. View Article : Google Scholar : PubMed/NCBI
92	Aslakson CJ and Miller FR: Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 52:1399–1405. 1992.PubMed/NCBI
93	Simões RV, Serganova IS, Kruchevsky N, Leftin A, Shestov AA, Thaler HT, Sukenick G, Locasale JW, Blasberg RG, Koutcher JA, et al: Metabolic plasticity of metastatic breast cancer cells: Adaptation to changes in the microenvironment. Neoplasia. 17:671–684. 2015. View Article : Google Scholar : PubMed/NCBI
94	Meyer MB, Benkusky NA, Kaufmann M, Lee SM, Onal M, Jones G and Pike JW: A Kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D 3 activation. J Biol Chem. 2017 Aug 14–2017.Epub ahead of print. View Article : Google Scholar
95	Anderson PH: Vitamin D activity and metabolism in bone. Curr Osteoporos Rep. 15:443–449. 2017. View Article : Google Scholar : PubMed/NCBI
96	Marik R, Fackler M, Gabrielson E, Zeiger MA, Sukumar S, Stearns V and Umbricht CB: DNA methylation-related vitamin D receptor insensitivity in breast cancer. Cancer Biol Ther. 10:44–53. 2010. View Article : Google Scholar : PubMed/NCBI
97	Banwell CM, O'Neill LP, Uskokovic MR and Campbell MJ: Targeting 1α,25-dihydroxyvitamin D3 antiproliferative insensitivity in breast cancer cells by co-treatment with histone deacetylation inhibitors. J Steroid Biochem Mol Biol. 89–90:245–249. 2004. View Article : Google Scholar
98	Khanim FL, Gommersall LM, Wood VHJ, Smith KL, Montalvo L, O'Neill LP, Xu Y, Peehl DM, Stewart PM, Turner BM, et al: Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Oncogene. 23:6712–6725. 2004. View Article : Google Scholar : PubMed/NCBI
99	Zhi H-Y, Hou S-W, Li R-S, Basir Z, Xiang Q, Szabo A and Chen G: PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization. Oncogene. 30:1706–1715. 2011. View Article : Google Scholar :
100	Krishnan AV, Swami S and Feldman D: Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: Importance of mammary CYP27B1 for treatment and prevention. J Steroid Biochem Mol Biol. 136:289–295. 2013. View Article : Google Scholar :
101	Swami S, Krishnan AV, Wang JY, Jensen K, Horst R, Albertelli MA and Feldman D: Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology. 153:2576–2587. 2012. View Article : Google Scholar : PubMed/NCBI
102	Jeong Y, Swami S, Krishnan AV, Williams JD, Martin S, Horst RL, Albertelli MA, Feldman BJ, Feldman D and Diehn M: Inhibition of mouse breast tumor-initiating cells by calcitriol and dietary vitamin D. Mol Cancer Ther. 14:1951–1961. 2015. View Article : Google Scholar : PubMed/NCBI
103	Rossdeutscher L, Li J, Luco A-L, Fadhil I, Ochietti B, Camirand A, Huang DC, Reinhardt TA, Muller W and Kremer R: Chemoprevention activity of 25-hydroxyvitamin D in the MMTV-PYMT mouse model of breast cancer. Cancer Prev Res (Phila). 8:120–128. 2015. View Article : Google Scholar
104	Ooi LL, Zhou H, Kalak R, Zheng Y, Conigrave AD, Seibel MJ and Dunstan CR: Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. Cancer Res. 70:1835–1844. 2010. View Article : Google Scholar : PubMed/NCBI