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Loss of oestrogen-receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. In 72 paired biopsies the immunohistochemical expression of ERs was reduced from 51% before tamoxifen treatment to 29% at progression or relapse, with a reduction in mean H-score from 90 to 61 (P<0.001, paired t-test). However, there was no significant change in progesterone receptor (PgR) or pS2 expression, markers of ER function. Tumours which developed acquired resistance after primary tamoxifen treatment frequently remained ER+ve at relapse (61%) and continued to express PgR or pS2. In contrast, those which progressed with de novo resistance were all ER\m=-\ve,although 6 of these tumours expressed high levels of PgR and/or pS2. In tumours which recurred during adjuvant tamoxifen therapy, the frequency and quantitative level both of ERs and of PgR were significantly reduced. These data imply that separate mechanisms of tamoxifen resistance may exist in these clinical subgroups.

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Abstract. The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through geneenvironment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.

No abstract