Aluminium and the human breast.

The human population is exposed to aluminium (Al) from diet, antacids and vaccine adjuvants, but frequent application of Al-based salts to the underarm as antiperspirant adds a high additional exposure directly to the local area of the human breast. Coincidentally the upper outer quadrant of the breast is where there is also a disproportionately high incidence of breast cysts and breast cancer. Al has been measured in human breast tissues/fluids at higher levels than in blood, and experimental evidence suggests that at physiologically relevant concentrations, Al can adversely impact on human breast epithelial cell biology. Gross cystic breast disease is the most common benign disorder of the breast and evidence is presented that Al may be a causative factor in formation of breast cysts. Evidence is also reviewed that Al can enable the development of multiple hallmarks associated with cancer in breast cells, in particular that it can cause genomic instability and inappropriate proliferation in human breast epithelial cells, and can increase migration and invasion of human breast cancer cells. In addition, Al is a metalloestrogen and oestrogen is a risk factor for breast cancer known to influence multiple hallmarks. The microenvironment is established as another determinant of breast cancer development and Al has been shown to cause adverse alterations to the breast microenvironment. If current usage patterns of Al-based antiperspirant salts contribute to causation of breast cysts and breast cancer, then reduction in exposure would offer a strategy for prevention, and regulatory review is now justified.

Benign breast diseases, contraception and hormone replacement therapy.

The term benign breast disease includes a wide and heterogenous spectrum of lesions different for histology and natural history. Approximately 70% of women who undergo a biopsy for benign breast disease have non-proliferative lesions with no increased risk of breast cancer, 26% have typical hyperplasia which is associated with a two-fold increased risk, and only 4% have atypical hyperplasia which is associated with a five-fold increased risk. The data on the effect of steroid hormones on benign breast disease come from observational studies with several potential bias. Most papers have reported that oral contraceptives protect against benign breast disease, whereas some others have suggested that effects of pill are not yet fully clear. As far as hormone replacement therapy (HRT) is concerned, some studies have shown an increased incidence of benign breast disease in long-term HRT users, whereas other investigations have found either no effect or a protective effect. The use of HRT does not appear to influence the clinical pattern of benign breast disease in postmenopausal women, although enlargement of pre-existing cysts or fibroadenomas has been sometimes reported. The limited available data failed to detect a deleterious effect of HRT use in women with benign breast disease, even in those with increased breast cancer risk due to a family history or high-risk benign breast conditions.

Environmental oestrogens, cosmetics and breast cancer.

The established role of oestrogen in the development and progression of breast cancer raises questions concerning a potential contribution from the many chemicals in the environment which can enter the human breast and which have oestrogenic activity. A range of organochlorine pesticides and polychlorinated biphenyls possess oestrogen-mimicking properties and have been measured in human breast adipose tissue and in human milk. These enter the breast from varied environmental contamination of food, water and air, and due to their lipophilic properties can accumulate in breast fat. However, it is emerging that the breast is also exposed to a range of oestrogenic chemicals applied as cosmetics to the underarm and breast area. These cosmetics are left on the skin in the appropriate area, allowing a more direct dermal absorption route for breast exposure to oestrogenic chemicals and allowing absorbed chemicals to escape systemic metabolism. This review considers evidence in support of a functional role for the combined interactions of cosmetic chemicals with environmental oestrogens, pharmacological oestrogens, phyto-oestrogens and physiological oestrogens in the rising incidence of breast cancer.

Do underarm cosmetics cause breast cancer?

Although animal and laboratory studies suggest a possible link between certain chemicals used in underarm cosmetics and breast cancer development, there is no reliable evidence that underarm cosmetics use increases breast cancer risk in humans. This article reviews the evidence for and against the possible link between breast cancer and underarm cosmetics and highlights the need for further research to clarify this issue.

Mammary fibroadenomatous hyperplasia in a young cat attributed to treatment with megestrol acetate.

A male, neutered cat was presented for lethargy, reluctance to walk, and mammary enlargement after recent treatment with megestrol acetate. Mammary fibroadenomatous hyperplasia was diagnosed on the basis of history, clinical signs, and histopathological findings. Pathogenesis, clinical signs, and treatment options for mammary fibroadenomatous hyperplasia attributed to megestrol acetate treatment are discussed.

Underarm cosmetics and breast cancer.

Although risk factors are known to include the loss of function of the susceptibility genes BRCA1/BRCA2 and lifetime exposure to oestrogen, the main causative agents in breast cancer remain unaccounted for. It has been suggested recently that underarm cosmetics might be a cause of breast cancer, because these cosmetics contain a variety of chemicals that are applied frequently to an area directly adjacent to the breast. The strongest supporting evidence comes from unexplained clinical observations showing a disproportionately high incidence of breast cancer in the upper outer quadrant of the breast, just the local area to which these cosmetics are applied. A biological basis for breast carcinogenesis could result from the ability of the various constituent chemicals to bind to DNA and to promote growth of the damaged cells. Multidisciplinary research is now needed to study the effect of long-term use of the constituent chemicals of underarm cosmetics, because if there proves to be any link between these cosmetics and breast cancer then there might be options for the prevention of breast cancer.

Are there differences in breast tissue as a result of hormone replacement therapy? Can BEST imaging distinguish these differences?

Although it has been speculated that estrogen therapy may promote changes in breast tissue that could lead to cancer, no information exists as to differences in breast tissue for women who do and do not take hormone replacement (HRT) therapy. This study seeks to determine if there are differences in the tissue of women taking HRT in contrast to those who do not and if these differences are apparent in cases of breast cancer, cellular atypia, fibrocystic (FCD) disease and normal breasts. A total of 327 non-pregnant, non-lactating, pre-menopausal women were enrolled in the study, including 139 women who were actively taking HRT and 188 women who never had taken HRT. Using breast enhanced scintigraphy test (BEST) imaging, differentiation of breast tissue was determined. The groups were then analyzed to determine the effect of hormone therapy within each category of breast tissue. Differentiation between normal, FCD, cellular atypia, and breast cancer represent statistically significant differences (p.001) in metabolic activity and vascularity as demonstrated by differences in both average count activity (ACA) and maximal count activity (MCA). The distinction between cellular atypia and infiltrating breast cancer was statistically (p.05) different when looking at the maximal activity. Normal breast tissue and breasts with FCD appear more homogenous with no statistical differences in variability in breast tissue. Tissue variability is statistically greater when localized processes, such as cellular atypia and breast cancer, are present. Differentiation of cellular metabolic activity in breast tissue can be statistically determined when looking at the average and maximal metabolic activity. The final distinction between cellular atypia and cancer occurs when a focal region of breast tissue becomes metabolically more active than the surrounding breast tissue as shown by statistical increases in MCA. These findings are confirmed by the increased metabolic variability seen in regions of cellular atypia and cancer compared with the homogenous metabolic activity present in normal and fibrocystic breasts.

Do women taking hormone replacement therapy (HRT) have a higher incidence of breast cancer than women who do not?

An estimated one third of all American and United Kingdom women take hormone therapy. In sharp contrast to these numbers, as many as one half of women diagnosed with breast cancer have taken hormones. Little additional information is available regarding the risk of breast cancer and even less is known about the association between hormone therapy and fibrocystic (FCD) disease or atypia of the breast. Three hundred women between 30 and 50 years of age were enrolled in this study, including 120 taking hormone replacement (HRT) therapy and 180 women who had never taken hormone therapy. These women were divided into four categories including those with normal breast tissue, those with FCD disease, those with cellular atypia, and those with breast cancer. Another group of women were also identified who had breast implants. Using breast enhanced scintigraphy (BEST) imaging, changes in breast tissue were determined and compared according to the use of HRT. Forty percent (122 of 300) had "normal" breasts, of whom 68.8% (84 of 122) did not take HRT. This accounted for 46.7% (84 of 180) of the women not taking hormone therapy, while only 31.7% (38 of 120) of the women taking HRT had normal breasts. This difference was statistically (p.001) significant. There was a greater incidence of breast abnormality in women taking HRT and a lower incidence in pathology among women not taking HRT when cumulatively analyzed for FCD, cellular atypia, and breast cancer. This difference was statistically significant (p.001) for women with breast cancer where 62.5% (10 of 16) were women taking HRT. Although the study was relatively small, it is the first such study to compare a continuum of changes in breast tissue according to the use of HRT. The study suggests that the initial empirical observations regarding higher incidence of HRT among women with breast cancer, may have a relationship to underlying changes in breast tissue that are associated with differences in mitochondrial content and activity. Further investigation is needed.

Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

BACKGROUND: The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). METHODS: Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. RESULTS: EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. CONCLUSIONS: There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens.

OBJECTIVE: The aim of this study was to evaluate the impact of different hormone replacement therapy (HRT) regimens on mammographic breast density. STUDY DESIGN: Mammographic density was recorded in women participating in a population-based screening program. At first mammogram, all women were non-users of HRT, and thereafter reported continuous use of the same HRT regimen. The study population comprised 158 women: a total of 52 women were using continuous combined HRT (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 5 mg); 51 women were using low-dose oral estrogen alone (estriol 2 mg daily); and 55 women were using unopposed transdermal estrogen given as a patch (estradiol 50 micrograms/24 h). Films were coded and analyzed for mammographic density by an independent radiologist blinded to treatments. Mammographic density was classified according to Wolfe. RESULTS: An increase in mammographic density was much more common among women taking continuous combined HRT (40%) than for those using oral low-dose estrogen (6%) and transdermal (2%) treatment. The increase in density was already apparent at the first visit after starting HRT. During long-term follow-up, there was very little change in mammographic status. CONCLUSION: HRT regimens were shown to have different effects on the normal breast. There is an urgent need to clarify the biological nature and significance of a change in mammographic density during treatment and, in particular, its relation to symptoms and breast cancer risk.

Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology.

OBJECTIVE: The aim was to evaluate fine-needle-aspiration (FNA) cytology as a method of following breast epithelial proliferation in postmenopausal women during hormone replacement therapy (HRT). METHODS: Twelve healthy postmenopausal women were recruited and randomized to two different types of sequential HRT during 4 months of treatment. The women were administered continuous estradiol 50 micrograms/24 h with the addition of progestogen sequentially in the form of either vaginal progesterone gel 8 mg every 2nd day or medroxyprogesterone acetate 5 mg/day orally during 12 days per month for the complete treatment period. Fine-needle-aspiration biopsies were performed twice during the estrogen phases and twice during the estrogen plus progestogen phases of treatment. Breast epithelial proliferation was analyzed in these samples by immunocytochemistry to measure the content of the nuclear antigen Ki-67/MIB-1, which is expressed in proliferating cells. RESULTS: From the 12 women, a total number of 47 FNA biopsies were taken. Thirty-eight of these aspirates, 19 from each of the estrogen and the estrogen plus progestogen phases, were evaluable for MIB-1 content (81%). There was a non-significant increase in levels of proliferation during the combined estrogen-progestogen phase (2.1%) compared with the estrogen-only phase (1.4%). These values were similar to those previously observed during the menstrual cycle in young fertile women. CONCLUSIONS: We conclude that the FNA biopsy technique is feasible for studying proliferation not only in young, normally cycling women but also in the postmenopausal breast.

Fibrous tumor of the breast in a postmenopausal woman receiving estrogen.

Fibrous tumor of the breast is a rare, benign stromal proliferation with atrophy of the epithelial component. Almost all patients who develop fibrous tumors are premenopausal. An unusual example of fibrous tumor of the breast is reported in a 62-year-old postmenopausal woman. The mass, first noted 1 year previously, progressively enlarged over the year. The patient noted a history of taking exogenous estrogens for 10 years. Intense estrogen administration during the year of enlargement may be associated with accelerated growth of the tumor. In addition, positive nuclear staining for estrogen receptor antibodies in stromal cells was demonstrated by immunohistochemical methods.

A cohort study of oral contraceptive use and risk of benign breast disease.

The purpose of the cohort study reported here was to investigate the association between oral contraceptive use and risk of benign breast disease (BBD), overall and by histological subtype, within the 56,537 women in the Canadian National Breast Screening Study (NBSS) who completed self-administered lifestyle and dietary questionnaires. The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment. Cases were the 2,116 women in the dietary cohort who were diagnosed with biopsy-confirmed incident BBD. For comparative purposes, a subcohort consisting of a random sample of 5,681 women (including 197 subjects with incident BBD) was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 2,116 cases and 5,338 non-cases. There was an inverse association between use of oral contraceptives and risk of all types of BBD combined. The reduction in risk was confined largely to proliferative forms of BBD (BPED), and in particular, to those forms of BPED without histological atypia, in whom there was a progressive reduction in risk with increasing duration of use (the IRR (95% CI) for use of more than 7 years was 0.64 (0.47-0.87)); risk of BPED with atypia was increased somewhat in association with oral contraceptive use (the IRR (95% CI) for use of more than 7 years was 1.43 (0.68-3.01 )), but not in a dose-dependent manner. The results were similar when examined separately in the screened and control arms of the NBSS and for screen-detected and interval-detected BPED.

PIP: This cohort study examined the association between oral contraceptive use and the risk of benign breast disease (BBD). The Canadian National Breast Screening Study (NBSS), which employed 56,837 women aged 40-59 who completed both lifestyle and dietary questionnaires, is a randomized controlled trial of screening for breast cancer. About 2116 cases in the dietary cohort were identified and diagnosed with biopsy-confirmed BBD. The study selected 5681 women from the dietary cohort, including 197 BBD subjects for comparative purposes. Results revealed an inverse association between oral contraceptive use and risk of all types of BBD. An examination by histological subcategory revealed that risk reduction is confined largely to proliferative forms of BBD and benign proliferative epithelial disorders (BPED) without histological atypia, and with a progressive risk reduction in relation to the increasing use duration [the IRR (95% CI) for more than 7 years of use was 0.64 (0.47-0.87)]. On the other hand, the increased risk of BPED with atypia was found to be correlated with contraceptive use [the IRR (95% CI) for more than 7 years of use was 1.43 (0.68-3.01)], but not in a dose-dependent manner. The result of a separate examination in the screened and control arms of the NBSS and for screen-detected and interval-detected BPED was similar. In conclusion, this study confirms the association of prolonged contraceptive use with reduced risk of proliferative forms of BPED without atypia and increased risk of BPED with atypia.

[Hormonal contraception and benign breast disease. Evaluation of a treatment protocol for chronic mastopathy with mastalgia]. / Contraccezione ormonale e patologia mammaria benigna. Valutazione di un protocollo di trattamento nella mastopatia cronica con mastalgia.

INTRODUCTION AND AIMS: The aim of this study was to study patients suffering from mammary nodules, fibrocystic disease and mastodynia. Having established the absence of malignant disease, the effect of EP (oestroprogestin) was evaluated in the treatment of fibrocystic disease with mastalgia. METHODS: From January 1990 to December 1995 a total of 1921 women underwent breast examination at the "Centro di Fisiopatologia della Mammella" in the Division of Gynecology and Obstetrics of Iseo Municipal Hospital. Subjects were aged between 9 and 84 years old. The experimental protocol included a retrospective study of a group of 89 patients suffering from chronic fibrocystic disease with mastalgia with a 3-month follow-up. The clinical examination was commenced by recording the patient's history and the measurement of the thickness of the gland and the evaluation of mastalgia represented important stages of the eco-clinical assessment. The setting for the study was the breast pathology out-patient clinic of the Division of Gynecology and Obstetrics. These women regularly attended our outpatient clinics for the following reasons: depistage, mastodynia, mammary secretion, self-diagnosis of mammary nodules, checkups in patients during follow-up after surgery for genital neoplasia. All patients underwent clinical, echographic and often mammography/X-ray. Patients were selected on the basis of the following criteria: absence of malignant pathology and presence of chronic fibrocystic disease with mastalgia. Of those admitted to the study (no. = 89), only 59 completed the course. In addition to the absence of malignant pathology and the presence of chronic fibrocystic disease with mastalgia, the following parameters were assessed: measurement of the thickness of the mammary gland involving QSE before and after 3-month treatment with EP. The EP used were: gestodene 0.075 mg and etynylestradiol 0.03 mg-Minulet, or etynylestradiol 0.02 mg and dexogestrel 0.150 mg-Securgin and Mercilon. RESULTS: The response to treatment was classified according to the 4 levels of the Cardiff Breast Score (CBS). The results were relatively good: 35.59% of patients showed a reduction in symptoms; 25.42% showed a marked improvement, and 18.64% a remission of symptoms. No effect was reported in 20.33% of patients. CONCLUSIONS: In conclusion, it may be said that EP treatment for 3 months can at least be proposed in patients with chronic fibrocystic disease and mastalgia given that a reduction and improvement in symptoms was seen in 60% of patients.

Keratinocyte growth factor causes cystic dilation of the mammary glands of mice. Interactions of keratinocyte growth factor, estrogen, and progesterone in vivo.

Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell proliferation that has been reported to induce marked proliferation of mammary epithelium in rats. In this study, systemic administration of KGF into naive and oophorectomized mice causes mammary gland proliferation, as evidenced histologically by the appearance of cysts lined by a single layer of epithelium and by hyperplastic epithelium. Whole mount preparations of the mammary glands reveal that the histologically noted cysts are actually ducts that are dilated along much of their length. The histology of the mammary glands of KGF-treated mice is similar to the histology of fibrocystic disease in the human female breast. The response in mice differs significantly from the appearance of the mammary glands in KGF-treated rats in which ductal epithelial proliferation is most prominent. Estrogen and progesterone when administered in combination but not alone cause the development of numerous endbuds in the mouse mammary gland. KGF in estrogen- and progesterone-pretreated mice causes the growth of dilated ducts, hyperplastic epithelium within ducts and endbuds, and a fibrous metamorphosis of periductal adipose tissue. The mammary epithelial hyperplasia caused by KGF is rapidly reversible in both mice and rats after cessation of KGF treatment. The spectrum of KGF-, estrogen-, and progesterone-induced mammary histopathology in mice provides a model for the study of fibrocystic and hyperplastic breast disease.

[Change in the glandular bodies of the breast after hormone therapy. Observations from the radiologic viewpoint]. / Anderung des Drüsenkörpers der Mammae nach Hormontherapie. Beobachtungen aus radiologischer Sicht.

In the last few years we have recognized a clear change in the mammograms in women undergoing hormone replacement therapy. Not all of them reacted in the same way: 30% on 366 treated patients showed a distinct glandular hyperplasia. Some developed nodes like cysts or adenomas, others had an increase in calcification as a sign of epithelia proliferation, as verified by histological examination. The opposite effect was seen in women receiving antioestrogen therapy as a consequence of breast-conserving therapy. The problems will be illustrated.