Raloxifene-stimulated experimental breast cancer with the paradoxical actions of estrogen to promote or prevent tumor growth: A unifying concept in anti-hormone resistance

Abstract

Abstract.We have previously demonstrated that prolonged treatments with raloxifene (RAL) in vitro will result in phase II RAL resistance and RAL-induced tumor growth. Clinical interest prompted us to re-examine RAL resistance in vivo, particularly the effects of long-term treatments (a decade or more) on the evolution of RAL resistance. In this study, we have addressed the question of this being a reproducible phenomenon in wild-type estrogen receptor (ER)-positive human breast cell line MCF-7. MCF-7 cells cultured under estrogen-deprived conditions in the presence of 1 μM RAL for more than a year develop RAL resistance resulting in an independent cell line, MCF7-RAL. The MCF7-RAL cells grow in response to both estradiol E 2 and RAL. Fulvestrant (FUL) blocks RAL and E 2 -mediated growth. Transplantation of MCF7-RAL cells into athymic ovariectomized mice and treatment with physiologic doses of E 2 causes early E 2 -stimulated tumor growth. In contrast, continuous treatment of implanted animals with daily oral RAL (1.5 mg daily) causes growth of small tumors within 15 weeks. Continuous re-transplantation of the tumors growing in RAL-treated mice indicated that RAL stimulated tumor growth. Tumors in the untreated mice did not grow. Bi-transplantation of MCF7-E 2 and MCF7-RAL tumors into the opposing mammary fat pads of the same ovariectomized animal demonstrated that MCF7-E 2 grew with E 2 stimulation and not with RAL. Conversely, MCF7-RAL tumors grew with RAL and not E 2 , a characteristic of phase II resistance. Established phase II resistance of MCF7-RAL tumors was confirmed following up to 7 years of serial transplantation in RAL-treated athymic mice. The ER· was retained in these tumors. The cyclical nature of RAL resistance was confirmed and extended during a 2-year evolution of the resistant phases of the MCF7-RAL tumors. The MCF7-RAL tumors that initially were inhibited by E 2 grew in the presence of E 2 and subsequently grew with either RAL or E 2 . RAL remained the major grow stimulus and RAL enhanced E 2 -stimulated growth. Subsequent transplantation of E 2 stimulated tumors and evaluations of the actions of RAL, demonstrated robust E 2 -stimulated growth that was blocked by RAL. These are the characteristics of the antiestrogenic actions of RAL on E 2 -stimulated breast cancer growth with a minor component of phase I RAL resistance. Continuous transplantation of the phase I RAL-stimulated tumors for >8 months causes reversion to phase II resistance. These data and literature reports of the cyclical nature of anti-androgen/androgen responsiveness of prostate cancer growth, illustrate the generality of the evolution of antihormonal resistance in sex steroid-sensitive target tissues.

Pharmacology and Molecular Mechanisms of Clinically Relevant Estrogen Estetrol and Estrogen Mimic BMI-135 for the Treatment of Endocrine-Resistant Breast Cancer

“…Raloxifene induces acquired resistance as evidenced by SERM-stimulated BC cell growth ( Liu et al, 2003 ; Balaburski et al, 2010 ) ( Fig. 2H ; Supplemental Figs.…”