The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.

http://cinjweb.umdnj.edu/sites/molmdweb/documents/connectivitymap.pdf

The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Purpose To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. Recommendations The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.

/pdf/american-society-of-clinical-oncology-college-of-american-33ect3oz8r.pdf

American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer

Publisher Summary This chapter reviews the biological actions of progesterone and progestin derivatives in normal physiology, cancer treatment, and contraception. Progesterone and estrogen act synergistically on the endometrial lining of the uterine cavity. In women following menses, the proliferative phase is under estrogen control and is characterized by true glandular growth. After ovulation, progesterone leads to further endometrial thickening characterized by an increase in cell size rather than number, increased tortuosity of the glands and arterioles, and glandular secretion. As the corpus luteum wanes, progesterone withdrawal and local prostaglandin synthesis lead to increased uterine contractility, vasospasm, endometrial desquamation, and bleeding. Progesterone also acts synergistically with estrogen in the normal development of the breast. Depending on the physiological state, progesterone may also antagonize estrogen action. Progesterone is a small, hydrophobic molecule that crosses the plasma membrane without impediment, and once inside the cells, binds tightly but reversibly to progesterone-receptor (PR) proteins. Binding of the hormone rapidly transforms the proteins by triggering a conformational change, so that they bind tightly to DNA and regulate the transcription of a small number of genes.

Chapter 14 Progesterone action and receptors

We propose that the molecular heterogeneity of ER in breast tumor cells characterized by the presence of mutant receptor forms generates the cellular heterogeneity evident when PR or DNA ploidy are analyzed in cell subpopulations. Furthermore, it is likely that cellular heterogeneity leads to the lack of uniformity in response to tamoxifen. We find that heterogeneity of PR distribution and DNA ploidy reflects existence of mixed subpopulations of breast cancer cells that are substantially remodeled under the influence of tamoxifen. It appears likely that rather than being "resistant, "different subsets of cells can be inhibited or stimulated by tamoxifen, and their suppression or outgrowth alters the phenotype of the tumor. PR heterogeneity in solid tumors of patients may predict for such a mixed, and potentially dangerous, response to antiestrogen treatment. Similarly, the molecular heterogeneity resulting from the presence of two normal PR isotypes can lead to inappropriate responses to progesterone antagonists in certain genes or cell types. These agonistlike responses are due to cooperative interactions between the receptors and other transcription factors. As we learn more about the heterogeneity of PR, ER, and other proteins in tumors, we may be able to recognize such lethal cell subpopulations or combinations of regulatory factors. Specifically, our data suggest, with respect to tamoxifen, that its use as a chemopreventant in women at high risk of developing breast cancer (Kiang 1991) should be viewed with caution, since in the presence of tamoxifen, subpopulations of cells may arise that are stimulated, rather than inhibited, by the drug.

Hormone-resistant breast cancer or "feeding the hand that bites you".

319 Progestins, antiprogestins and progesterone receptors in breast cancer: Mechanisms and biological actions

Antiestrogens and human breast cancer: effects and mechanisms of action

In estrogen target tissues and hormone-dependent tumors the steroid enters the cells and binds to a cytoplasmic protein called the estrogen receptor (ER). The steroid-receptor complex then migrates to the nucleus where it initiates the characteristic biochemical events. ER receptor was assayed in 600 human breast tumors for correlation with response to endocrine therapy. The values in primary tumors have ranged from 0 to almost 1000 femtomoles/mg of cytosol protein. Positive values have been found in 70% of primary specimens and in 58% of metastatic material. Since endogenous estradiol would occupy ER sites and make them unavailable for assay this may account for the wide range of values and for the highest values in postmenopausal patients. For clinical correlation of response to endocrine therapy 8 institutions were visited and a total of 531 treatment trials in 453 patients were reviewed. Complete agreement between the records and the reviewers evaluations was obtained in 442 of the 531 treatment trials. In all but 17 cases of disagreement inadequate documentation was the cause. With castration adrenalectomy or hypophysectomy 33% of 211 treatment trials resulted in objective tumor regression. Of 197 trials in patients with positive ER values 59 (55%) were favorable while in patients with negative ER values only 8% were successful. Patients with borderline tumor ER values had a 30% response rate. Thus many patients can be spared unrewarding ablative endocrine therapy if ER assays are done routinely. Additive therapy with estrogens androgens or glucocorticoids produced a 34% regression rate in 170 cases. Of those with positive tumor ER values 60% showed tumor regression while only 8% of those with negative ER tumor values did so. Other endocrine therapies as antiestrogens aminoglutethimide resulted in favorable responses in 27% of 55 trials. Of 23 trials in patients with positive ER values 43% succeeded but only 16% of those with negative ER tumor values did so. Coupled with other clinical factors endocrine therapy can be selected or rejected with relative confidence. It was thought that tumors with ER but no pregesterone receptor (PgR) would be resistant to endocrine therapy. The presence of PgR was also investigat ed in over 100 tumors. PgR was absent in all of the tumors lacking ER. Of the ER-positive tumors 6% had PgR. Thus the additional presence of PgR provides a more accurate marker of hormone dependence. Preliminary data in support of this hypothesis are encouraging.

Hormone receptors and endocrine therapy in human breast cancer.

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