Her-2/neu and INT2 Proto-oncogene Amplification in Malignant Breast Tumors in Relation to Reproductive Factors and Exposure to Exogenous Hormones

Abstract

In previous studies in southern Sweden, early use of oral contraceptives has been found to be accompanied by an increased risk of developing premenopausal breast cancer, and the tumors developing in these patients have shown a more aggressive behavior. In the present study, amplification of the proto-oncogenes Her-2/neu (also known as ERBB2) and INT2 was studied in primary tumor specimens from 72 premenopausal women and was related to starting age of oral contraceptive use and other reproductive risk factors. Amplification of Her-2/neu was more common among early oral contraceptive users (i.e., those starting at less than or equal to 20 years of age) than among nonusers or late users (odds ratio [OR], 5.3; 95% confidence interval [CI], 1.6-16.7), whereas INT2 amplification did not differ significantly among those groups (OR, 0.9; 95% CI, 0.1-5.0). The likelihood of INT2 amplification was greater among users of progestins and those with a history of abortions before the first full-term pregnancy (OR, 9.0; 95% CI, 1.3-51.7; and OR, 18.6; 95% CI, 2.2-165.8, respectively). No significant relationships were found between proto-oncogene amplification and the variables of parity, age at first full-term pregnancy, or late abortion. The increased ORs persisted after adjustment for age at diagnosis and other risk factors. The findings suggest that the higher rate of Her-2/neu amplification among early oral contraceptive users is an effect of the oral contraceptive use per se rather than of the relative youth of the users. Moreover, the relationship between progestin use and early abortion and amplification of the INT2 gene is biologically plausible.

A case-control study of reproductive variables, alcohol, and smoking in premenopausal bilateral breast cancer

“…However, the variables investigated here have not previously been shown to affect survival, but several have been shown to affect incidence in previous studies of breast cancer; therefore, any apparent risk factors found here likely reflect these variables' effect on incidence rather than on survival. One possible exception is for OCs, which have recently been associated with a somatic mutation of the Her-2 oncogene that is associated with poorer prognosis [10]. If this association is real and strong, it may have caused a conservative bias (towards the null) for the OC effect in our data.…”

Cyclin D1 expression is dependent on estrogen receptor function in tamoxifen-resistant breast cancer cells

“…Cyclin D1 expression has been correlated with ER levels in breast cancer, suggesting that ER is a key regulator of cyclin D1 expression in primary breast tumors [22,23]. In addition, amplification of the cyclin D1 gene occurs almost invariably in ER-positive breast cancer, suggesting that ER and cyclin D1 cooperate in driving tumor growth [23][24][25]. Furthermore, overexpression or amplification of cyclin D1 has been shown to predict early relapse and poor prognosis in ER-positive tumors [25][26][27][28].…”

An observational study on the incidence of HER-2/neu receptor over-expression and comparison of clinical presentation between HER-2/neu positive and HER-2/neu negative breast cancer

“…This is in agreement with various studies where HER-2/neu or its protein P185 is over-expressed in 10-35% of breast cancer patients in the western population an over amplification of this gene in 25-30%, have been reported. [8][9][10] Age at presentation…”