The etiology and prediction of breast cancer. Fourier transform-infrared spectroscopy reveals progressive alterations in breast DNA leading to a cancer-like phenotype in a high proportion of normal women.

BACKGROUND: The authors previously have shown by gas chromatography-mass spectrometry that the hydroxyl radical (.OH) induces alterations in the DNA base structure of the female breast, which are premalignant markers of breast cancer. Fourier transform-infrared (FT-IR)-spectroscopy also has a high potential for revealing a broad array of structural changes in DNA that may provide important new insight into breast cancer etiology and prediction. METHODS: DNA from normal reduction mammoplasty tissue, invasive ductal carcinoma, and nearby microscopically normal tissue was analyzed by FT-IR spectroscopy. Statistical models based on DNA spectral properties were developed and compared with a statistical model previously used with base modifications. RESULTS: Substantial differences were found in the spectral properties of DNA from women with normal and cancerous breast tissue, indicating an ability to discriminate cancerous tissue from noncancerous tissue with a sensitivity and specificity of 83%. Most importantly, the normal population was divided into subgroups in which a nonrandom progression was identified and a cancer-like DNA phenotype that was highly correlated (r > or = 0.90) with that of the patients with cancer was exhibited in 59% of the women. The spectral data, which also were highly correlated with the base-model data, were used to establish a model for predicting the probability of breast cancer. Consistent with the high cancer reoccurrence rate in the ipsilateral breast, 8 of 10 of the microscopically normal tissue specimens remaining after tumor excision were classified as cancerous using this model. CONCLUSIONS: Progressive structural changes in the DNA of the normal female breast, leading to a premalignant cancer-like phenotype in a high proportion of women, are the basis for a new paradigm for understanding the etiology of breast cancer and predicting its occurrence at early stages of oncogenesis. The results also suggest therapeutic strategies for potentially reversing the extent of DNA damage, which may be useful in disease prevention and treatment.

Relation of membrane property of microsomes to androgen biosynthesis.

Spin-labelled fatty acids I(12,3) and I(1,14) were incorporated into microsomal membrane of cryptorchid mouse testis and Leydig cell tumor as well as liver. The freedom of motion of spin of I(12,3) was more restricted in testis microsome than in liver. At the lower temperatures, the freedom of motion of spin in the tumor microsomes was similar to that in the testis, but at higher temperature (20-50 degrees C) was much greater. Plotting of the empirical parameter, h0/h-1, calculated by the spectra of I(1,14), against the reciprocal of the absolute temperature clearly showed two inflection points in both liver and testis microsomes, one at 19 decrees C and the other at 30 degrees C. On the other hand, tumor microsomes lacked these break points and permitted spin to move more freely. These results suggest that tumor microsomes contain the increased fluidity. The importance of membrane fluidity in relation to steroid biosynthesis was also discussed.

Electron spin resonance studies of erythrocytes from patients with Duchenne muscular dystrophy.

The membrane organization of the erythrocytes from patients with Duchenne muscular dystrophy was studied by means of electron spin resonance. The fluidity of the membrane near the polar region of Duchenne muscular dystrophy erythrocytes was similar to that of normal erythrocytes. The membrane environment in the nonpolar region, however, was quite different from that of normal erythrocytes, judged by the spectra with 2-(14-carboxytetradecyl) - 2 - ethyl - 4,4 - dimethyl - 3 - oxazolidinyloxyl as probe. The temperature dependence of the ratio of the line height of central field to that at the low field showed two inflection points in normal erythrocytes at pH 7.4 (13.5 degrees -16.5 degrees and 37.5 degrees -40.5 degrees C, respectively) but the inflection point in the lower temperature range was not detected in Duchenne muscular dystrophy erythrocytes. When pH was varied, an abrupt decrease in the ratio was observed at pH 5.9-5.6 in normal erythrocytes whereas there was a gradual decrease over the range of pH from 6.6 to 5.0 in Duchenne muscular dystrophy erythrocytes. The rate of reduction of the radical 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl by ascorbate in normal erythrocytes was faster than that in Duchenne muscular dystrophy erythrocytes. Treatment of both erythrocytes with phloretin markedly reduced the rate of reduction by ascorbate and eliminated the difference in the two types of erythrocyte. These results indicate that in Duchenne muscular dystrophy the erythrocyte membrane is involved as well as the muscle cell.