Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure.
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 SHBG gene results in an amino acid substitution (Asp327Asn), which introduces an additional N-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 (P<0.05). To get insight into the underlying mechanisms, we compared the ability of recombinant wild type and variant (D327N) SHBG to influence estradiol effects in MCF-7 breast cancer cells. D327N SHBG was more effective than wild type 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 wild type protein. As a consequence, D327N caused a larger induction of the second messenger cAMP and a deeper inhibition of the estradiol-induced Erk (1/2) 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.
Costantino
Lucia
L
Laboratory of Oncological Endocrinology, ASO San Giovanni Battista, Via Genova 3, Turin 10126, Italy.
Catalano
Maria G
MG
Frairia
Roberto
R
Carmazzi
Carlo M
CM
Barbero
Maggiorino
M
Coluccia
Claudio
C
Donadio
Michela
M
Genta
Franco
F
Drogo
Mauro
M
Boccuzzi
Giuseppe
G
Fortunati
Nicoletta
N
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012738:Sex Hormone-Binding Globulin / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction
D004967:Estrogens; D012738:Sex Hormone-Binding Globulin; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases