Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion

In estrogen receptor (ER) positive breast cancer cells such as MCF-7 cells, the anti-tumor effects of 1,25(OH) 2D 3 (1,25D 3) may be secondary to disruption of estrogen mediated survival signals. If so, then sensitivity to 1,25D 3 mediated growth arrest could be reduced in estrogen independent breast cancer cells. The aim of these studies was to determine the effects of 1,25D 3 and EB1089 on the ER negative, invasive human breast cancer cell line SUM-159PT. 1,25D 3 and EB1089 reduced SUM-159PT cell growth subsequent to elevation of p27 and p21 levels. 1,25D 3 mediated apoptosis of SUM-159PT cells was associated with an enrichment of membrane bound bax, a redistribution of cytochome c from the mitochondria to the cytosol and PARP cleavage. 1,25D 3 and EB1089 also inhibited SUM-159PT cell invasion through an 8 μM Matrigel membrane. In pre-clinical studies, EB1089 dramatically reduced the growth of SUM-159PT xenografts in nude mice. The decreased size of tumors from EB1089 treated mice was associated with decreased proliferation and increased DNA fragmentation. Our data support the concept that Vitamin D 3 compounds trigger apoptosis by mechanisms independent of estrogen signaling. These studies indicate that Vitamin D 3 based therapeutics may be beneficial, alone or in conjunction with other agents, for the treatment of estrogen independent breast cancer.