BRCA1/2 associated hereditary breast cancer

Abstract

Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes, focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial; further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

INTRODUCTION

Although the advancement of diagnostic techniques and treatment in the last decade has greatly contributed to the survival of cancer patients, breast cancer is still one of the leading causes of death in women today. It is estimated that there are approximately 180 510 new occurrences of breast cancer and 40 910 breast cancer deaths (40 460 women, 450 men) in the year of 2007 in the US (American Cancer Society, 2007). Among breast cancer patients, up to 5%~10% are considered directly relating to the inheritance of mutation in BRCA1 or BRCA2 (Claus et al., 1996), which accounts for most of the hereditary breast cancers. Moreover, women carrying these mutations have a lifetime breast cancer risk of 60%~80% (Easton et al., 1993; Struewing et al., 1996); therefore, detection of mutation in these two genes can serve as a molecular predictor for women with a family history of breast cancer.

As a consequence of current trends in multidisciplinary therapy for breast cancers, BRCA1 and BRCA2, like other genes, have not only served as molecular markers for hereditary breast cancer risk screening, but also become important indicators for breast cancer prevention, treatment and prognosis. In this review, we provide an overview of these two well-known breast cancer susceptibility genes, focusing on their relationship with hereditary breast cancers.

FUNCTIONS AND MUTATIONS

BRCA1 was first located to chromosome 17 via a genetic linkage analysis in 23 early-onset breast cancer families (Hall et al., 1990), and was cloned and isolated in 1994 (Miki et al., 1994). Further research had localized it to 17q21 with a length of 100 kb. BRCA1 has 24 exons, including 2 non-translating exons, encoding a protein of 1 863 amino acids, which is characterized by a zinc-binding RING-finger domain at the amino terminus and BRCA1 carboxyl-terminal (BRCT) domain at the carboxyl terminus.

BRCA1 is classified as a tumor suppressor gene and plays an important role in surveillance of cell cycle and repair of DNA damage. Evidence shows that BRCA1 is phosphorylated by the checkpoint kinase ataxia telangiectasia mutated (ATM) protein after ionizing radiation (Cortez et al., 1999). Mediator of DNA damage checkpoint protein 1 (MDC1) can regulate BRCA1 to the sites of DNA lesions and phosphorylate it through ATM dependent pathways (Lou et al., 2003). After activation, BRCA1 can bind to p53, RAD50-MRE11-NBS1 (R-M-N) complex and RAD51, conducting homologous recombination or non-homologous end-joining (NHEJ) which is of great importance in DNA damage repair. The zinc-binding RING-finger domain of BRCA1 can interact with BRCA1 associated RING domain 1 (BARD1) forming a heterodimeric complex that has ubiquitin ligase activity (Hashizume et al., 2001), and the complex itself may be involved in DNA damage repair.

In 1995, a second gene termed BRCA2 was found related to hereditary breast cancer (Wooster et al., 1995). It covers about 70 kb of genomic sequence in 13q12, encoding a protein of 3 418 amino acids. The coding region of BRCA2 is composed of 27 exons with a non-translating exon. However, the gene sequence of BRCA2 bears no obvious homology to any known gene including BRCA1, and the protein contains no defined functional domains (Tavtigian et al., 1996; Wooster et al., 1995). BRCA2 can bind with BRCA1, participating in DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair (Chen et al., 1999).

For their key role in maintaining genomic integrity and supervising cell cycle, mutations in BRCA1 and BRCA2 are found strongly related to hereditary breast cancers. However, the types of mutation differ in distribution by ethnicity and geographic location. The “hot spot” sites of mutation for Ashkenazi Jewish are present at 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 (Abeliovich et al., 1997), whereas 3171ins5 is the characterized mutation from high-risk families examined in Sweden (Einbeigi et al., 2001). The prevalence of mutations in BRCA1 and BRCA2 also varies in diverse populations. For example, the BRCA1 mutation frequency in Finnish breast cancer patients is 0.4% (Syrjakoski et al., 2000), whereas by contrast the number for its neighbor country, Sweden, is 7% (Zelada-Hedman et al., 1997). Among all the genetic alterations in BRCA1 and BRCA2, 85% are frameshift or nonsense mutations, yielding a truncated protein product (Struewing et al., 1995). The cells, therefore, have a decreased ability to repair damaged DNA; the genomic instability is observed in animal models due to this defect (Yu et al., 2000). Tumor tissues from carriers of mutant BRCA1 or BRCA2 gene are presented with chromosomal abnormalities including losses of 5q, 4q, 4p, 2q, 12q, 13q and 6q significantly more commonly than the normal control group (Tirkkonen et al., 1997).

PATHOLOGY

Hereditary breast cancers arising in carriers of BRCA1 and/or BRCA2 genes mutations differ from sporadic breast cancers of age-matched controls and from non-BRCA1/2 hereditary breast carcinomas in their morphological, immunophenotypic and molecular characteristics. BRCA1 associated breast carcinomas have the “basal-like” phenotype (Perou et al., 2000), a subtype of high grade (usually Grade 3), high mitotic count, estrogen receptor (ER) and Her2 negative carcinomas (Breast Cancer Linkage Consortium, 1997; Lakhani et al., 1998), characterized by the expression of basal or myoepithelial markers such as basal keratins (Foulkes et al., 2003), P-cadherin, epidermal growth factor receptor, etc. (Honrado et al., 2005). BRCA1 associated breast carcinomas usually have the over-expressions of the cell-cycle proteins such as cyclins A, B1 and E, and S-phase kinase-associated protein 2 (SKP2) (Honrado et al., 2005). BRCA2 associated breast carcinomas are rarely that “basal-like” phenotype, but a subtype that has higher grade (usually Grade 2/3) than sporadic age-matched controls (Breast Cancer Linkage Consortium, 1997), and tend to be ER and progesterone receptor (PR) positive (Lakhani et al., 2002; Robson et al., 2004). BRCA2 associated breast carcinomas usually have the over-expressions of cyclin D1 and p27 (Honrado et al., 2005). Recent studies have shown that non-BRCA1/2 associated breast cancers tend to have lower grades and mitotic counts than BRCA1/2 associated hereditary breast cancers (Honrado et al., 2005).

PREVENTION

Penetrance refers to the probability of developing disease in a carrier of a deleterious mutation and is usually detected at a given age. It appears that the risk of cancer among women who carry a BRCA1 or BRCA2 mutation could be modified by some specific genes or by an environmental factor and lifestyles. In the case of hereditary breast cancers, the candidate modifier genes that have been studied are related to the metabolism of sex hormones and to DNA repair. Four genes, Androgen Receptor (AR), Nuclear Receptor Coactivator 3 (NCOA3), RAD51 and H-ras, have been suggested as potential modifiers of risk in BRCA1 or BRCA2 mutation carriers, but the evidence for these is too weak to guide clinical practice (Narod, 2002). Hormonal factors (oophorectomy, pregnancy, breastfeeding, oral contraceptives, tubal ligation, tamoxifen, hormone replacement therapy, etc.) have also been tried to modify the risk of breast cancer. Some studies indicate that oophorectomy reduces risk in BRCA1 mutation carriers and probably in BRCA2 mutation carriers, whereas tamoxifen reduces the risk in BRCA2 mutation carriers (King et al., 2001) and probably in BRCA1 mutation carriers (Narod et al., 2000), although ER status is usually negative in those BRCA1 mutation carriers.

Women with a BRCA1 or BRCA2 mutation who have a high risk of breast cancer could choose to undergo prophylactic bilateral total mastectomy, which reduces the incidence of breast cancer at three years of follow-up (Meijers-Heijboer et al., 2001). In another study, data indicate that the majority of women reported satisfaction with bilateral prophylactic mastectomy; in the meantime, they experienced psychosocial outcomes similar to those with similarly elevated breast cancer risk who did not undergo prophylactic mastectomy. Bilateral prophylactic mastectomy appears to have neither positive nor negative impact on long-term psychosocial outcomes (Geiger et al., 2007). According to recent research results, women who are BRCA1/2 mutation carriers and have a history of breast cancer or ductal carcinoma in situ (DCIS), or a family history of ovarian cancer, are more likely to have undergone surgical procedures for risk reduction (Uyei et al., 2006). At present, it is much more difficult to develop risk-assessment tools to take into consideration all established risk factors including mutation type and position, reproductive history, exogenous hormone level, and the specific relevant modifying genes.

PROGNOSIS

Prognosis of patients carrying mutant BRCA1 or BRCA2 compared with general breast cancer populations still remains controversial. Several studies have proved that patients with BRCA1 mutation have poor outcome. A research program at collaborating centers in Norway and the UK found that the five-year survival in BRCA1-mutated patients is 73% compared to 92% in mutation-negative patients (P<0.001) (Moller et al., 2007). One study from 496 Jewish women with breast cancer showed a similar result that the rate of breast cancer specific survival after a median follow-up period of 116 months is worse for BRCA1 mutants than for non-carriers (62% vs 86%, P<0.0001) (Robson et al., 2004). On the contrary, some studies reported no significant differences of survival data existing between women with BRCA1 mutations and those without. One study on Israeli women concluded that breast cancer specific rates of death are similar between carriers of a BRCA1/2 founder mutation and non-carriers, with the hazard ratio among BRCA1 carriers to be 0.76 and 95% confidence interval (CI) 0.45~1.30, P=0.31; and the hazard ratio among BRCA2 carriers to be 1.3 and 95% CI 0.80~2.15, P=0.28 (Rennert et al., 2007). Another two studies conducted in New York and Rotterdam presented the same negative results that breast cancer specific survival is similar between the mutation carriers and non-carriers in breast cancer patients and patients at high risk for breast cancer, respectively (El-Tamer et al., 2004; Brekelmans et al., 2006).

Because of the controversial results, whether there is a real difference in survival data remains unclear. More attention is needed to examine the variable factors, such as ER status, lymph node involvement, and cancer staging.

SUMMARY

About one decade has passed since the discovery of the BRCA1/2 genes, and we have come to realize the constructions and major functions of BRCA1/2 proteins and also the close relationship between BRCA1/2 mutations and hereditary breast cancers. BRCA1/2 genes are tumor suppressor genes, the mutations of which could result in hereditary breast cancers. Several measures have been tried to reduce the risk of hereditary breast cancers. The initial results after prophylactic oophorectomy/bilateral prophylactic mastectomy and oral administration of tamoxifen show their effects on risk reduction. BRCA1/2 associated breast cancers have their own pathologic characteristics. However, prognosis of patients carrying mutant BRCA1/2 compared with general breast cancer populations still remains controversial. The further elucidation on the relationship between BRCA1/2 mutations and hereditary breast cancer remains a task in the future.