It has been demonstrated that in humans certain factors such as early menarche, late pregnancy, and nulliparity are associated with a higher risk of developing breast cancer, while early pregnancy acts as a protective factor. Induction of mammary cancer in rats by administration of the chemical carcinogen 7, 12-dimethylbenz(a)anthracene reveals that the same factors influencing human breast cancer risk also affect the susceptibility of the rat mammary gland to the chemical carcinogen. Nulliparous rats and rats undergoing pregnancy interruption are more susceptible to developing carcinomas. This fact has been attributed to the incomplete differentiation of the gland at the time of carcinogen administration. Parous rats are resistant to the carcinogenic effect of DMBA, which is explained by the complete development of the gland attained during pregnancy and lactation. This development is manifested by the differentiation of terminal end buds into secretory units, which have a smaller proliferative compartment; the epithelial cells of these secretory units have a longer cell cycle, less avidity for binding DMBA, and possess a more efficient DNA excision repair capacity.

Differentiation of the mammary gland and susceptibility to carcinogenesis

Summary of Suggestions for Future Directions This brief review of results of recent epidemiological investigations suggests some additional approaches for future studies. First, the studies of the DES-exposed women and of oral contraceptive users suggest that the timing of exposure may be critical, since the possible effect of both these hormonal agents may be limited to specific time periods of rapid breast development. Studies of other possible etiological agents should also try to focus more on exposures during critical time periods. On the other hand, if such a critical period does not exist in postmenopausal women, then there may be little effect of hormones used at this time. Instead, exposure to higher than average levels of estrogen from estrogen replacement therapy or through greater conversion to estrogen in adipose tissue in obese women may result in only a modest elevation in risk and only after prolonged exposure, because of the relative inactivity of the breast at the time of exposure. Also, the effect of radiation and the possible effects of estrogen replacement therapy and oral contraceptives remind us of the long latency period that may be necessary before an effect is seen for at least some agents. Thus, studies with long-term follow-up and that include long-term users are important in studies of effects of hormones and other exposures. Among the newly hypothesized etiological agents, it would seem that the possible protective effect of physical activity merits further study. An effect of physical activity has not been well studied in the past, and possible biological mechanisms have been postulated. With regard to alcohol, assessment of the influence of age when consumption began and duration of exposure as well as the identification of plausible mechanisms of action would aid in clarifying the role of alcohol consumption in breast cancer etiology. Ongoing studies of benign breast diseases are aimed at addressing the question of subgroups at particularly high risk, and ongoing studies of radiation are addressing such questions as the risks from low-dose exposures and the latency period following exposure. The results of these studies will be awaited with interest. Since it is virtually certain that endogenous sex hormones play a role in breast cancer etiology, continued study of their role with new and improved measurement techniques is obviously of high priority. Likewise, in those cases of breast cancer in which marked familial aggregation is seen, newly developed probes for marker genes will be useful. Finally, it is also likely that exposures not studied to date are involved in breast cancer etiology, since known risk factors by no means account for the entire risk of breast cancer. Thus, new ideas are needed, particularly regarding exposures at critical time periods.

https://cancerres.aacrjournals.org/content/canres/48/20/5615.full.pdf

Breast Cancer Epidemiology

Allele loss on short arm of chromosome 17 in breast cancers.

Background. A family history of breast cancer reflects shared cultural factors, genetic predisposition, or both. There is evidence that the estimated risk associated with a family history of breast cancer increases multiplicatively in combination with other risk factors. We examined the combined effect of family history and anthropometric and reproductive factors on the risk of breast cancer in postmenopausal women. Methods. Using data from a prospective cohort study, we studied 37,105 women 55 to 69 years of age to determine whether known risk factors for breast cancer are modified by a reported family history at the time of entry into the study. Results. During the first four years of follow-up, 493 new breast cancers were diagnosed. The association of the waist-to-hip ratio (the circumference of the waist divided by that of the hips) with the risk of breast cancer was limited predominantly to women with a family history of breast cancer; the age-adjusted relative risk of breast cancer for the ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199205143262004

Effect of Family History, Body-Fat Distribution, and Reproductive Factors on the Risk of Postmenopausal Breast Cancer

To investigate whether a family history of breast cancer increases a woman's risk of developing breast cancer, we analyzed data from the Centers for Disease Control's Cancer and Steroid Hormone Study. The 4,735 cases were women 20 to 54 years old with a first diagnosis of breast cancer ascertained from eight population-based cancer registries; the 4,688 controls were women selected at random from the general population of these eight areas. Compared with women without a family history of breast cancer, women who had an affected first-degree relative had a relative risk of 2.3; women with an affected second-degree relative had a relative risk of 1.5; and women with both an affected mother and sister had a relative risk of 14. The risk of breast cancer for a woman was higher if her first-degree relative had unilateral rather than bilateral breast cancer or had breast cancer detected at a younger rather than older age. For women aged 20 to 39, 40 to 44, and 45 to 54 years, the estimated annual incidence of breast cancer per 100,000 women attributable to a first-degree family history of breast cancer was 51.9, 115.1, and 138.6, respectively, and that attributable to a second-degree family history of breast cancer was 12.1, 19.2, and 92.4, respectively. ( JAMA 1985;253:1908-1913)

Family History and the Risk of Breast Cancer

A Genetic Study of Human Breast Cancer

This is a historical cohort study of breast cancer mortality in the Mexican-American community of Laredo, Texas. Included in this study were virtually all breast cancer deaths recorded in Laredo since 1875; controls matched to cases by age and birth year were drawn from the total population. Fertility history and family history of disease for cases and controls were retrieved from the genealogical data base reconstructed by our group from church and civil records for the whole city of Laredo. The findings of this study show an association between breast cancer risk and age at first birth. This study confirms familial risk to be a factor in breast cancer risk. Unlike postmenopausal breast cancer mortality in the total U.S. population, which has increased only slightly in the last 30-40 years, postmenopausal breast cancer death rates in Laredo have almost tripled since the 1940's.

Epidemiology of Breast Cancer in a Mexican-American Population

Cancer control can be improved through the application of knowledge of the hereditary aspects of certain malignant and premalignant disorders. A concrete example of the effectiveness of the application of genetic knowledge has been demonstrated by study of a family wherein five of seven siblings manifested xeroderma pigmentosum. Knowledge of the hereditary aspects of this disorder and its discovery in one sibling led to the immediate detection of the disorder in other siblings. In turn, preventive measures were instituted toward the avoidance of exposure to the carcinogenic effects of sunlight. Genetic counseling alleviated anxiety and major misconceptions among the family members concerning the hereditary aspects of this disorder.

David E. Anderson

Papers

A Genetic Study of Human Breast Cancer

Epidemiology of Breast Cancer in a Mexican-American Population

Cancer, heredity and genetic counseling. Xeroderma pigmentosum