cholesterol-alpha-oxide and Breast-Neoplasms

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Breast Neoplasms; Carcinogens; Cell Line; Cell Line, Tumor; Cholesterol; Epoxide Hydrolases; Estrogen Receptor alpha; Female; HEK293 Cells; Humans; MCF-7 Cells; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Receptors, Glucocorticoid; RNA, Messenger

We measured levels of cholesterol and its oxidation products, 5,6 alpha- and beta-epoxides and their common hydrolysis product cholestane triol, in breast fluids of women without breast disease, compared these levels to serum cholesterol levels, and explored associations of these breast fluid measurements with known breast cancer risk factors and other characteristics. Subjects were 105 women with no history of breast disease from whom breast fluid could be obtained by nipple aspiration. The four breast fluid measurements were significantly correlated with each other (P less than 0.0001) but none was correlated with serum cholesterol. In subsequent analyses restricted to breast fluid cholesterol and cholesterol beta-epoxide, cholesterol levels (but not beta-epoxide levels) increased with age and were higher in white than nonwhite women. Both measurements were low in women who were lactating, who were parous, or who had breast-fed. The lower levels among parous women persisted for at least 2 years postpartum or postlactation. Because breast fluid levels of cholesterol beta-epoxide are reduced for some time following a birth or cessation of lactation, the alveolar-ductal systems of parous women presumably have less cumulative exposure to this potentially carcinogenic substance. This biochemical mechanism may, in part, explain the observed reduction of breast cancer risk associated with parity.

Topics: Adult; Age Factors; Aged; Body Height; Body Weight; Breast; Breast Neoplasms; Cholesterol; Exudates and Transudates; Female; Humans; Middle Aged; Risk Factors; Smoking

In nipple aspirates of breast fluid from nonpregnant healthy women, cholesterol and cholesterol epoxide levels were determined with gas-liquid chromatography and mass spectrophotometric techniques. Cholesterol levels were found to be elevated above plasma levels averaging 2200 +/- 1995 (S.D.) mg/dl and showing progressive increases in mean breast fluid cholesterol levels with advancing age, averaging 187, 1957, and 3554 mg/dl in women of age groups 20 to 29, 30 to 39, an 40 to 49 years, respectively. Cholesterol epoxide was detected in a significant number of women who yielded high levels of breast fluid cholesterol. Cholesterol epoxide has been reported by other workers to have transforming activity for embryo hamster cells and to be carcinogenic in animals. The findings lend support to our hypothesis and observation that the human breast secretes mutagenic and cancer-promoting substances which may have relevance in studies of the etiology of benign breast disease and cancer.

Topics: Adult; Age Factors; Aging; Body Fluids; Breast; Breast Neoplasms; Carcinogens; Cholesterol; Female; Gas Chromatography-Mass Spectrometry; Humans; Middle Aged