Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 239

Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.

In the United States, 10–20% of patients with breast cancer and patients with ovarian cancer have a first- or second-degree relative with one of these diseases. The familial tendency to develop these cancers is called hereditary breast–ovarian cancer syndrome. The best known of these are the BRCA mutations. Some mutations associated with cancer, such as p53, BRCA1, and BRCA2, occur in mechanisms to correct errors in DNA. These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs. However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families. This is caused by unobserved risk factors. This implicates environmental and other causes as triggers for breast cancers. The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA double strand breaks. These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2. However, mutations in BRCA genes account for only 2–3% of all breast cancers. Levin et al. say that cancer may not be inevitable for all carriers of BRCA1 and BRCA2 mutations. About half of hereditary breast–ovarian cancer syndromes involve unknown genes.

GATA-3 directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.

Most breast cancers that arise in the setting of a germline mutation in BRCA1 are triple negative (i.e., they do not express any hormonal receptors like estrogen, progesterone, or HER2/neu receptors, hence triple negative). Patients with triple-negative breast cancer that is diagnosed at 60 years or younger undergo BRCA mutation testing regardless of family history. Some genetic susceptibility may play a minor role in most cases. Overall, however, genetics is believed to be the primary cause of 5–10% of all cases. In those with zero, one, or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1%, with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6%, respectively. In those with a first-degree relative with the disease, the risk of breast cancer between the ages of 40 and 50 is double that of the general population.

In less than 5% of cases, genetics plays a more significant role by causing a hereditary breast–ovarian cancer syndrome; this includes those who carry the BRCA1 and BRCA2 gene mutation. These mutations account for up to 90% of the total genetic influence, with a risk of breast cancer of 60–80% in those affected. Other significant mutations include p53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), STK11 (Peutz–Jeghers syndrome), CHEK2, ATM, BRIP1, and PALB2.

Because of the role of BRCA1 in DNA damage response and cell cycle checkpoint control, it is believed that BRCA1-associated breast cancer will be sensitive to certain DNA-damaging agents, such as platinum agents (carboplatin or cisplatin). In one clinical trial of BRCA1 mutation carriers presented at the 2011 Annual Conference of Hereditary Cancers, 67 women with stage I to III breast cancer were treated with cisplatin for four cycles prior as neoadjuvant treatment; the pathologic complete response was 67%. However, survival results were not presented. While these results support the sensitivity of BRCA1-associated cancer to platinum salts, they must be considered hypothesis generating. More compelling evidence supports a role for poly ADP ribose polymerase (PARP) inhibition in BRCA1/2 carriers.