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D C Allred, S K Mohsin, and S A Fuqua

Most human invasive breast cancers (IBCs) appear to develop over long periods of time from certain pre-existing benign lesions. Of the many types of benign lesions in the human breast, only a few appear to have significant premalignant potential. The best characterized of these include atypical hyperplasias and in situ carcinomas and both categories are probably well on along the evolutionary pathway to IBC. Very little is known about earlier premalignant alterations. All types of premalignant breast lesions are relatively common but only a small proportion appear to progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect epidemiological evidence. Although lesions within specific categories look alike, they must possess underlying biological differences causing some to remain stable and others to progress. Recent studies suggest that they evolve by highly diverse genetic mechanisms and research into these altered pathways may identify specific early defects that can be targeted to prevent premalignant lesions from developing or becoming cancerous. It is far more rational to think that breast cancer can be prevented than cured once it has developed fully. This review discusses histological models of human premalignant breast disease that provide the framework for scientific investigations into the biological alterations behind them and examples of specific biological alterations that appear to be particularly important.

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S A W Fuqua, C Wiltschke, C Castles, D Wolf, and D C Allred


We have isolated an estrogen-receptor (ER)-variant mRNA from ER-negative/progesterone receptor (PgR)-positive human breast cancers. This variant lacks exon 5 of the hormone-binding domain, resulting in a truncated receptor protein which is unable to bind estrogen. In vitro experiments show that the exon 5 variant possesses constitutive ER activity. For example, when transfected into ER-negative MDA-MB-231 breast cancer cells, it stimulates an estrogen-responsive element (ERE)-dependent reporter system in the presence or absence of exogenous hormone. Proliferation is unaffected by the antiestrogen tamoxifen, which usually inhibits the growth of MCF-7 cells, suggesting that the exon 5 variant may be important clinically in drug resistance. Preliminary studies have found expression of the exon 5 variant transcript in ER-positive breast cancers, but these studies need to be expanded to detect the protein in tumors. It is also possible that ER variants which influence cell proliferation may be involved in carcinogenesis. In this context, we have identified a novel ER variant in a preliminary survey of hyperplastic lesions which are thought to be precursors of invasive breast cancer. This variant possesses a single base-pair alteration in the hormone-binding domain, and exhibits enhanced stimulation of an ERE-reporter system when cotransfected into MDA-MB-231 breast cancer cells. We are currently evaluating its prevalence in premalignant breast lesions, and its ability to influence cell proliferation.

Endocrine-Related Cancer (1995) 2 19-25

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M Dowsett, S Johnston, L-A Martin, J Salter, M Hills, S Detre, M C Gutierrez, S K Mohsin, J Shou, D C Allred, R Schiff, C K Osborne, and I Smith

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.