Abstract
Breast cancers are a major cause of mortality in females, on a par with lung and colon cancers. One topic in this chapter are the causes of breast cancer, environmental risk factors as well as genetic predisposition, conferred by high-risk mutations in hereditary cancer syndromes, like hereditary breast and ovarian cancer caused by germline mutations in homologous recombination repair (HRR) genes, and by prevalent low-risk genetic variants. Therapy of breast cancer has been substantially advanced by subtyping based on molecular characteristics and by consequentially targeted therapies, providing a paradigm for other carcinomas. Breast cancer molecular subtypes differ in gene expression patterns, genetic alterations, cellular origin, prognosis, and response to specific therapies. Hormone receptor-positive tumors retain expression of the Estrogen receptor α and express markers of luminal mammary epithelial cells. They remain dependent on estrogens for growth and survival and can be treated by anti-estrogenic therapies, with differences between luminal A and luminal B cancers. HER2+ breast cancers are driven by gene amplification and overexpression of ERBB2. These cancers respond well to targeted therapy employing specific antibodies and tyrosine kinase inhibitors. Breast cancers lacking hormone receptors and ERBB2 overexpression are classified as triple-negative. Within this heterogeneous group, basal-type cancers have the highest frequency of TP53 and BRCA1 mutations. Triple-negative breast cancers are treated by cytotoxic chemotherapy, with PARP inhibitors as an additional option in cancers with mutations in HRR genes. Finally, invasive lobular mammary carcinomas are distinguished by loss of E-Cadherin and a diffuse-type growth pattern.
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Notes
- 1.
See Box 5.2 for cervical carcinoma, a frequent cancer in females in some other regions of the world.
- 2.
In Western countries, menopause currently occurs in almost all women between the age of 45 and 55.
- 3.
Variants in risk genes for hereditary breast and ovarian cancer are cataloged and classified by several research consortia, see www.esmo.org
- 4.
Subtyping of breast cancers may be further detailed by also considering patterns of chromosomal changes, in addition to gene expression and mutation data. Such classifications, such as METABRIC, require however integration of data from different technology platforms and are therefore difficult to implement broadly in clinical practice.
- 5.
Remarkably, even though only a fraction of the cancer cells may express the Estrogen receptor. The cut-off in histological diagnostics is 1% of the cells positive.
- 6.
And may further depend on the relative expression of ERβ, which has different binding affinities for tamoxifen and other SERMs.
- 7.
Protac stands for “proteolysis targeting chimera”; these molecules consist of two parts one binding to the target the other to a ubiquitin ligase, connected by a linker. They are mostly in clinical trials or under development at the time of writing.
- 8.
Often resulting in separated structures within the cell. The assemblies are therefore characterized as “phase transitions” and may contain (noncoding) RNAs as well as proteins.
- 9.
A compound similar to cisplatin with generally better tolerable adverse effects.
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Schulz, W.A. (2023). Breast Cancer. In: Molecular Biology of Human Cancers. Springer, Cham. https://doi.org/10.1007/978-3-031-16286-2_19
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