Premalignant breast lesions: role for biological markers in predicting progression to cancer.

Biological markers associated with in situ carcinoma and atypical intraductal hyperplasia in the breast are examined to help in identifying a subgroup of premalignant lesions whose natural history may be influenced by epigenetic factors. The biomarkers may be used as indices in clinical trials aiming to assess the effect of weight reduction, dietary intervention or hormone replacement therapy on the risk of progression to invasive breast cancer. In the current state of knowledge, the expression of oestrogen receptors, p53, bcl-2 and HER-2 neu oncogenes and the Ki-67 index of proliferative activity, are the most useful biomarkers for this purpose. In situ carcinoma of the breast manifests a variety of morphological phenotypes with specific biological characteristics. There is evidence that only a proportion of premalignant lesions are committed to progression to invasive cancer while other lesions undergo spontaneous regression at the time of the menopause. Cross-cultural studies suggest that it is the late-stage epigenetic promoting factors which are responsible for the high incidence of postmenopausal breast cancer in Western women. Obesity in middle life and the Western diet favour the development of hyperinsulinaemic insulin resistance, and the metabolic-endocrine effects of its concomitants may promote mammary carcinogenesis around the time of the menopause and increase the incidence of invasive cancer after the menopause. Because biomarker changes in premalignant lesions are nearer in time to these promoting influences, they could provide intermediate endpoints for testing the hypothesis.

Breast cancer and the western diet: role of fatty acids and antioxidant vitamins.

Epidemiological reports are inconsistent on the association between breast cancer risk and the dietary intake of either individual fatty acids or of antioxidant vitamins. It is postulated here that the inconsistencies are in part due to interactions between the two classes of nutrients at the level of the cell membrane, affecting their potential role in mammary carcinogenesis. In this review, the effects of specific dietary fatty acids and antioxidant vitamins on experimental mammary cancer systems are compared with reported epidemiological associations of the same agents with breast cancer risk in humans. An increased ratio of n-3 to n-6 polyunsaturated fatty acids (PUFAs) in the diet inhibits the growth of the rat mammary cancer model. There is also evidence that members of the n-3 PUFA series can inhibit the growth of human breast cancer cells both in vitro and in explants. Clinical trials of supplementary n-3 PUFAs in conjunction with a reduced fat intake have been proposed for breast cancer prevention. It is postulated that further dietary supplementation with vitamin E and a retinoid is likely to increase the effectiveness of such a diet. A study of this type allows better control of specific dietary components than prospective trials of dietary fat reduction which are presently under evaluation. In particular, it is suggested that studies focusing on a single nutrient often fail to recognise interactions with other nutrients.

Impaired ovulation and breast cancer risk.

Conflicting results have been reported on the association between breast cancer risk and symptoms of luteal insufficiency, such as irregular or prolonged menstrual cycles and difficulty in becoming pregnant. Studies on the association between breast cancer risk and hormonal markers of impaired ovulation have also yielded conflicting results. Inadequate allowance for body mass and fat distribution may lead to inconsistent results when assessing the association between luteal insufficiency in premenopausal women and breast cancer risk. Ovulatory function is impaired by obesity, especially if it is predominantly abdominal in distribution. The Western diet and lifestyle favour early manifestation of hyperinsulinaemic insulin resistance in genetically-predisposed women. It is commonly associated with obesity which is predominantly abdominal in distribution. In a subset of premenopausal women, the concomitants of hyperinsulinaemia may impair maturation of ovarian follicles by a direct effect of insulin or insulin-like growth factors on ovarian tissue. Even when women are ovulating regularly, obesity may be associated with luteal insufficiency as shown by decreased levels of progestins or other changes in the sex steroid profile. Insulin resistance is likely to be involved and might explain the weak reduction in breast cancer risk associated with overweight in premenopausal Western women, in contrast with the increased risk widely reported in obese post menopausal women.

Alcohol intake and late-stage promotion of breast cancer.

Breast cancer risk in women rises with increasing alcohol intake and is widely assumed to be mediated by increased oestrogen concentrations. However, observations that mechanisms and risk are likely to differ between pre- and postmenopausal women suggest that the postmenopausal disease in particular, may involve a promoting role for concomitants of hyperinsulinaemia which is commonly associated with alcoholic cirrhosis of the liver. The MEDLINE database and ongoing studies were examined for clinical, epidemiological and laboratory data on; (a) alcohol-related increase in the incidence of breast cancer in relation to menopausal status, oestrogen concentrations and the oestrogen receptor (ER) status of the tumour; (b) activation of insulin-like growth factor 1 receptor (IGF1R) in mammary tissue by alcohol-related hyperinsulinaemia; (c) interaction between ER and IGF1R in breast cancer cell systems. Epidemiological association between alcohol intake and increased breast cancer risk is more clearly seen in postmenopausal than premenopausal women, and a significant risk is associated with intake of more than two drinks (over 30 g) daily over a period of years. Alcohol-related hyperinsulinaemia is reported to increase with increasing degrees of cirrhosis and damage to liver function. Laboratory evidence suggests that hyperinsulinaemia can stimulate expression of IGF1R in mammary tissue, and this protein is likely to have a crucial role in mitogenesis and transformation to an oestrogen-independent malignant phenotype. It is postulated that in women with a history of long-term intake of moderate quantities of alcohol, the concomitants of hyperinsulinaemia may help to stimulate progression in precancerous breast lesions in the years leading up to the menopause and may increase the risk of breast cancer manifesting after the menopause.

Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention.

Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined.

Biological mechanisms in breast cancer invasiveness: relevance to preventive interventions.

Migration studies suggest that the high incidence of postmenopausal breast cancer in Western women is related mainly to epigenetic factors. Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) also appears to involve environmental rather than genetic factors, and a role has been postulated for metabolic-endocrine changes related to the Western lifestyle. Protein kinase C (PKC) is important in cell signal transduction, and laboratory studies show that PKC stimulates the activities of urokinase plasminogen activator, matrix metalloproteinases and cell adhesion molecules, all of which are known to increase invasiveness in human mammary cancer cell lines. In rodents, the activity of PKC in tissue cells is enhanced by insulin, and PKC isoenzymes have been shown to stimulate the development of hyperinsulinaemic insulin resistance in rodents. Clinically, hyperinsulinaemia and the concomitant increase in circulating levels of free oestradiol and bioactive insulin-like growth factor 1 (IGF1) are each confirmed markers of high risk for breast cancer in women. Lesions of DCIS show evidence of regression with mammary involution, but it is postulated that this may be opposed by the concomitants of hyperinsulinaemic insulin resistance. The prevalence of the latter is increasing in Western populations, and a combination of high IGF1 and low IGF-binding protein 3 concentrations has been associated with the presence of DCIS lesions in premenopausal women. Measures that enhance insulin sensitivity in such women may reduce the risk of progression in DCIS lesions, and a clinical trial is proposed to test the hypothesis.

Quantifying the risk of breast cancer.

Although all women are potentially breast cancer sufferers, we need to develop a risk index in order to recognize the most vulnerable. Multiple promoting factors are suspected in breast cancer and recent research suggests that different types of clinical risk factor may interact to multiply a women's risk. Such women require skillful counselling with more frequent monitoring and advice about possible protective measures.

Western nutrition and the insulin resistance syndrome: a link to breast cancer.

OBJECTIVE: The incidence of breast cancer in the Western world runs parallel to that of the major components of the insulin resistance syndrome--hyperinsulinaemia, dyslipidaemia, hypertension and atherosclerosis. Evidence is reviewed that the growth of breast cancer is favoured by specific dietary fatty acids, visceral fat accumulation and inadequate physical exercise, all of which are thought to interact in favouring the development of the insulin resistance syndrome. DESIGN: Clinical, epidemiological and experimental studies linking breast cancer risk with evidence of insulin resistance and its concomitants, were searched for in the MEDLINE database since 1985. RESULTS: Clinical and epidemiological evidence suggests that both breast cancer and the metabolic disorders comprising the insulin resistance syndrome are polygenic and multifactorial in origin. Experimental evidence suggests that hyperinsulinaemia and its concomitants can increase the promotion of mammary carcinogenesis and the mechanism is likely to involve increased bioactivity of insulin-like growth factor 1 (IGF-1). Case-control and cohort studies have shown that higher serum levels of IGF-1 are associated with increased breast cancer risk. Pharmacological agents which lower IGF-1 concentrations are under clinical trial for breast cancer prevention. CONCLUSIONS: Nutritional and lifestyle modifications that improve insulin sensitivity may not only decrease a tendency to atherosclerosis but also reduce breast cancer risk in women. In addition to a reduced fat intake, the dietary regimen might involve a reduced n-6/n-3 ratio of polyunsaturated fatty acids and should be associated with avoidance of obesity and regular physical exercise. Interventions to decrease breast cancer risk in first-degree relatives of breast cancer patients need to begin at an early age.

Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk.

OBJECTIVE: Dietary supplements of the adrernocertical hormone dehydroepiandrosterone (DHEA) are widely taken in the hope of staving off the aging process. Potential dangers have not been fully researched, particularly evidence of a correlation between increased serum concentrations of DHEA and higher breast cancer risk in postmenopausal women. DESIGN: The review examines reports of clinical, epidemiological experimental studies for evidence that DHEA may be a factor in promoting the growth of mammary cancer. Biological mechanisms which might be involved are identified. RESULTS: DHEA is reported to inhibit the growth of human mammary cancer cells in vitro and also the growth of chemically-induced mammary cancer in rats. However, growth inhibition occurs only in the presence of high oestrogen concentrations, and growth stimulation occurs in both models in the presence of a low-level oestrogen milieu. Epidemiological studies report a positive correlation between higher serum concentrations of DHEA and increased breast cancer risk in the case of postmenopausal but not premenopausal women. Postulated mechanisms include a direct effect on mammary cells by androgenic metabolites of DHEA or an indirect effect by an increase in bioavailable oestrogen levels. The increased serum concentration of free insulin-like growth factor 1 which follows prolonged DHEA intake may also have a role by stimulating oestrogen receptor activity in breast tissue. CONCLUSION: Late promotion of breast cancer in postmenopausal women may be stimulated by prolonged intake of DHEA, and the risk may be increased by the endocrine abnormality associated with pre-existing abdominal obesity. Caution is advised in the use of dietary supplements of DHEA particularly by obese postmenopausal women.

Macronutrient supplements may reduce breast cancer risk: how, when and which?

OBJECTIVE: To examine evidence that specific fibre-associated macronutrients are associated with a decreased breast cancer risk. To review possible mechanisms, the age group when dietary intervention might be most effective and the choice of a suitable dietary supplement. DESIGN: This review distinguishes specific hormone-metabolic effects of dietary composition from those of body mass and fat distribution, in relation to the age at which they exert major effects on breast cancer risk. RESULTS: Both obesity and a high-fat/low-fibre diet in Western women may be associated with increased estrogen levels which are widely assumed to increase the risk of developing breast cancer. Both obesity and the Western diet are likely to stimulate insulin resistance, leading to increased levels of bioavailable estrogen. The concomitants of hyperinsulinemia may synergize with estrogen in stimulating progression of pre-neoplastic lesions in the breasts of late pre-menopausal women. Increased intake of fibre-associated macronutrients may reduce insulin resistance in addition to reducing the circulating levels of estrogen. CONCLUSIONS: The effect of dietary intervention on breast cancer risk in Western women may be tested in pre-menopausal women over the age of 40 y, with evidence of atypical hyperplasia in a breast biopsy. The most suitable fibre-associated macronutrient is still problematical but soy protein constituents have been shown to inhibit the growth of rat mammary cancer models and also of human breast cancer cell line in the laboratory.

Approaches to breast cancer prevention.

It may be possible to delay the step-by-step progression towards frank invasive cancer by avoiding one or more of the well-known clinical risk factors. In addition current clinical trials in the USA and Europe are assessing whether the use of tamoxifen, vitamin analogues or a low-fat diet can delay the appearance of overt disease in women known to be at high risk, but it will be several years before such trials can be evaluated. For women seeking advice on prevention, non-toxic supplements to the diet such as beta-carotene, vitamin A analogues or selenium compounds, and the avoidance of alcohol and obesity, are examples of practical advice which can do no harm yet may help to protect against breast cancer development. In the case of the very anxious first degree relative of a breast cancer patient, the current choice lies essentially between regular monitoring, mastectomy with reconstruction, early termination of ovarian activity and anti-oestrogen therapy. Currently, considerable research is being directed towards identifying oncogenes and growth factors which are involved in the growth of breast cancer. In the meantime, more research needs to be devoted to the effect of various progestagens in counteracting oestrogen support of breast cancer growth, and to biological observations on different formulations and doses of combined oestrogen/progestagen preparations which may reduce breast cancer risk both in pre- and postmenopausal women.

Selection of young women with high-risk breast cancer for adjuvant systemic therapy.

Biological criteria of tumour aggressiveness have recently been recommended for use in selecting high-risk cases for adjuvant systemic therapy after primary treatment of breast cancer. Without them, the clinician has considerable difficulty in balancing the morbidity of cytotoxic therapy against the possible benefits. Consistent evidence that patients under the age of 35 years have the worst prognosis of all age groups, while those in the 45-49 age group have the best prognosis, should help in a decision on suitable adjuvant treatment for either node-positive or node-negative young women with breast cancer.

Medical treatment of breast cancer.

Medical treatment is potentially more important than surgical treatment for the large majority of patients presenting withe breast cancer. Since each patient has unique characteristics affecting both tumour aggressiveness and host defence, a generalised approach to medical treatment is no longer acceptable.

[Selective mechanisms of hormonal therapy]. / Izbiratel'nye mekhanizmy gormonal'noi terapii.

PIP: Recent studies concerned the origin and treatment of mammary gland cancer are reviewed, with special attention to mechanisms of hormonal therapy. The comparative roles of prolactin and estrogens in originating mammary gland cancer and the relationship between activity of sex hormones and the presence of special target receptors are described. The role of estrogen receptors depending on their sensitivity to hormones is stressed, and several possible mechanisms of hormonal sensitivity are pointed out. Different mechanisms of originating mammary gland cancer and hormonal methods for cancer treatment are discussed. The focus is placed on understanding hormonal antagonism, cell metabolism and immunological reactions for this kind of cancer. The role of emotional stress in the pathogenesis and treatment of cancer is touched upon.^ieng

Endocrine therapy in cancer.

PIP: A proportion of cancers in endocrine target tissues can show the presence of specific receptors for either steroid or polypetide hormones. Manipulation of the controlling hormones does not guarantee regression. A third of cancers in endocrine target organs (breast, uterine endometrium, and prostate) show a 50% reduction in size of lesions after hormonal therapy. If regression resulting from an aggressive form of therapy lasts a short while and the tumor reactivates by the time the unpleasant effects of the therapy wear off, the treatment is not palliative. Endocrine therapy in prostatic cancer is palliative but there is no evidence that is increases survival. 11 different progestational agents in endometrial cancer therapy in the past 25 years resulted in a 30-35% response. Response must be maintained by continual treatment and may last from 12 months to 7-8 years. In breast cancer, tumors with a significant level of estrogen receptor (ER+) have about a 60% chance of regression vs. tumors without estrogen receptors (ER-), 10%. Advanced cancers of the thyroid of the papillary or follicular type regress when the patient is treated by thyroxine, .3 mg daily. Leukemia and lymphoma are frequently treated, with varying degrees of success with corticosteroid therapy, which may also predispose the patient to intercurrent infection. Renal cancer has been often treated by medroxyprogesterone acetate or testosterone propionate, with little success.^ieng