Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure

Lucia Costantino (1) , Maria G. Catalano (2) , Roberto Frairia (2) , Carlo M. Carmazzi (3) , Maggiorino Barbero (3) , Claudio Coluccia (4) , Michela Donadio (5) , Franco Genta (6) , Mauro Drogo (6) , Giuseppe Boccuzzi (1, 2) , Nicoletta Fortunati (1)

1 Laboratory of Oncological Endocrinology
2 Department of Clinical Pathophysiology
3 Division of Gynaecology
4 Division of Senology
5 Division of Medical Oncology
6 ASL1-Ospedale Evangelico Valdese

Sex Hormone-Binding Globulin, the specific carrier for sex steroids, regulates hormone bioavailable fraction and estrogen signaling system in breast cancer cells. A common single nucleotide polymorphism in the human gene results in an amino acid substitution (Asp327Asn), which introduces an additional -glycosylation site, and is associated with reduced breast cancer risk in postmenopausal women. The frequency of this polymorphism was evaluated in a group of patients that developed breast cancer while taking hormonal replacement therapy (HRT) for menopause, an interesting model of estrogen exposure. The polymorphism frequency was significantly higher in women taking HRT that didn't develop any breast cancer than in breast cancer patients ( < 0.05). To get insight into the underlying mechanisms, we compared the ability of recombinant and variant (D327N) SHBG to influence estradiol effects in MCF-7 breast cancer cells. D327N SHBG was more effective than protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis. This depended on the fact that D327N SHBG binding to MCF-7 cells was significantly higher than that of protein. As a consequence, D327N caused a larger induction of the second messenger cAMP and a deeper inhibition of the estradiol-induced Erk ½ phosphorylation. Our observations, demonstrating the increased efficiency of D327N SHBG in counteracting estradiol action and a significantly higher frequency of Asp327Asn polymorphism in women not developing breast cancer after estrogen exposure, first provide evidence for the mechanism of D327N SHBG protective action.

Mots clés: D327N SHBG; SHBG polymorphism; Breast cancer; Estrogens; cAMP; Erk

Lucia Costantino, Maria G. Catalano, Roberto Frairia, Carlo M. Carmazzi, Maggiorino Barbero, et al.. Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure. Breast Cancer Research and Treatment, 2008, 114 (3), pp.449-456. ⟨10.1007/s10549-008-0031-4⟩. ⟨hal-00478497⟩