Andrey Nailor, M.D.·Published 13 June 2008·14 min read
Key points
A number of genes have been identified as putative oncogenes in breast cancer based on expression in breast cancer and correlation with prognosis or as tumor suppressor genes by LOH.
C-myc is amplified in about 20% of breast cancers (Garcia et al., 1989; Berns et al., 1992).
The road to cancer in the breast may take many routes.
ErbB-1 ErbB-1 encodes for the 170-kDa protein epidermal growth factor receptor (EGFR).
A number of genes have been identified as putative oncogenes in breast cancer based on expression in breast cancer and correlation with prognosis or as tumor suppressor genes by LOH. A genetic sequence of events has been deduced for colon carcinoma (Fearon and Vogelstein, 1990). Although it is generally believed that breast cancer, too, is the culmination of numerous genetic alterations, a genetic sequence involved in progression for breast has not been deciphered.
The road to cancer in the breast may take many routes. Perhaps complementation groups such as those described for immortahzation (Pereira-Smith and Smith, 1988) exist such that one gene increases the probability of cancer only in the presence of second, specific genetic alteration(s). Undoubtedly genes yet to be identified, as well as the genes to be discussed, are involved.
ErbB-1 ErbB-1 encodes for the 170-kDa protein epidermal growth factor receptor (EGFR). More than 5% of cells overexpress EGFR in 56% of early invasive breast cancers, and expression may be associated with early relapse (Gasparini et al., 1992). In particular, cases that are EGFR positive with a growth fraction exceeding 7.5% as determined by antibody against Ki-67 are much more likely to relapse.
EGFR may be overexpressed in about 25% of DCIS cases (Moller et al., 1989), but a possible role in the development of PBD is suggested by the report that EGFR was detected more frequently in breast smears of complex breast cyst fluids (12/17) than in smears of simple cyst fluids (5/23; Athanassiadou et al., 1992). Simple cysts are those with flattened epithelium and complex cysts have apocrine or hyperplastic epithelium. The prevalence of overexpressed EGFR in fine-needle aspirates obtained from high risk patients (35%) was significantly greater than from women of low risk (4%; Fabian et al., 1994). High risk patients were defined as those with a first-degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. There is also evidence that overexpression of EGFR is common in fibroadenomas (Zelada-Hedman et al., 1994).
An association of EGFR expression and p53 expression has been described leading to the suggestion that the two interact in the pathogenesis of cancer (Horak et al., 1991). In that study, p53-positive tumors (staining-detectable with Pab240) were found to have a mean concentration of 31 fmol EGFR per mg of membrane protein compared to 14 fmol/mg for p53-negative tumors.
However, nearly half of the p53-positive cases were EGFR negative. A number of studies have found a negative correlation between expression of EGFR and ER (Sainsbury et al., 1987; Horak et al., 1991; Koenders et al., 1991) but many cases express both receptors (Koenders et al., 1991). The latter study found that, although erbB-1 levels decreased with increasing ER levels, 173/531 cases (33%) expressed both using at least 10 fmol/mg cytosolic protein as the criterion for ER status and 0.5 fmol/mg of membrane protein as the criterion for EGFR expression (median values were 40 fmol/mg).
Written and revised by
Andrey Nailor, M.D.
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Using different criteria (5 fmol/mg for ER and 3 fmol/mg for EGFR), 25% of normal breast samples and 33% of benign/fibrocystic samples were found to be positive for both ER and EGFR (Barker et al., 1989). However, individual cells within breast cancers apparently are never positive for both (Sharma et al., 1994). Thus, EGFR and ER expression appear to be mutually exclusive at the cellular level.
Normal breast epithelium, fibrocystic disease, and fibroadenomas all stained with weak to moderate intensity with antibodies to both erbB-2 and EGFR (Tsutsumi et al., 1990). Invasive carcinomas overexpressed one or the other, but not both, in 13 of 36 cases. In a single case, both erbB-2 and EGFR were overexpressed but in a reciprocal manner in which erbB-2 was overexpressed in the DCIS component and the EGFR was overexpressed in the invasive component (Tsutsumi et al., 1990).
Based on this case, the authors suggest that erbB-2 loss at the stage of invasion might explain the decrease in incidence of erbB-2 expression in invasive cancer from DCIS. However, this case seems to be the rare exception (see below). Both erbB-2 and EGFR were detected in only 6/126 breast cancers by immunohistochemistry, but these patients had significantly worse prognoses than did patients with invasive cancers expressing one or the other or neither (Toi et al., 1994). This study did not address whether EGFR and erbB-2 were detected in the same or separate cells within the six EGFR+/erbB-2+ cancers. {pagebreak}
ErbB-2 The erbB-2 gene encodes for a 185-kDa receptor tyrosine kinase with homology to the epidermal growth factor receptor erbB-1, erbB-3, and erbB-4. The natural ligand for erbB-2 has not been identified, but erbB-2 phosphorylation may occur by transmodulation when other members of the erbB kinase family react with their ligands (e.g., epidermal growth factor; Akiyama et al., 1988; Stern and Kamps, 1988; Johnson et al., 1993) and neu differentiation factor (Culouscou et al., 1993; Plowman et al., 1993; Carraway et al., 1994; Kita et al., 1994; SUwkowski et al., 1994; Tzahar et al., 1994). This transmodulation occurs through heterodimerization of erbB-2 with the other kinases.
Although overexpression of erbB-2 is associated with poor prognosis in human breast cancer, erbB-2 is rarely detected in benign lesions (De Potter et al, 1989; Lizard-Nacol et al., 1995; Millikan et al., 1995). ErbB-2 is not overexpressed in either lobular CIS (Gusterson et al., 1988b; Ramachandra et al., 1990; Porter et al., 1991) or invasive lobular carcinoma (Porter et al., 1991; Barbareschi et al., 1992).
However, overexpression of erbB-2 is frequent in DCIS and invasive ductal carcinoma. The precipitous rise in expression at the stage of DCIS suggests that overex-pression of erbB-2 may be sufficient to produce this step in progression.
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Although erbB2 is detected in DCIS more frequently than in invasive cancer (Gusterson etal., 1988a, b; De Potter etal., 1989; Kobayashietal., 1992), studies of mixed lesions containing both in situ and invasive components invariably report that the two components express erbB-2 coordinately (Ramachandra et al., 1990; Liu et al., 1992; Iglehart et al., 1995).
Thus, DCIS in which erbB-2 is not amplified gives rise to invasive carcinoma in which erbB-2 is not amplified and DCIS in which erbB-2 is amplified gives rise to invasive carcinoma in which erbB-2 is amplified. Since erbB-2 is not amplified in the majority of invasive breast cancers, these data suggest that DCIS in which erbB-2 is not amplified is more likely to progress to invasive carcinoma than is erbB-2-positive DCIS. The latter conclusion is somewhat counterintuitive because erbB-2 expression by invasive breast cancer is associated with poor prognosis (Slamonetal., 1987,1989; Paiketal., 1990; Gullick et al., 1991; Gustersonet al, 1992; Sauer et al., 1992). If erbB-2-expressing DCIS had a poor prognosis as indicated by more rapid/frequent progression to invasive cancer, the incidence of erbB-2 expression might be expected to be higher in invasive cancer than in DCIS.
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Both the incidence of erbB-2 amplification and the propensity of DCIS lesions to progress to invasive cancer vary with the histotype of DCIS. Comedo DCIS is more frequently erbB-2-positive than is cribriforming DCIS (Bartkova et al., 1990; Ramachandra et al., 1990). Ramachandra and colleagues found that 19% of pure cribriforming DCIS and 55% of mixed lesions containing both cribriforming in situ and invasive components expressed erbB-2. On the other hand, 62% of pure comedo DCIS lesions were erbB-2-expressing compared to only 49% of mixed lesions (Ramachandra et al., 1990).
These results indicate that erbB-2-positive cribriforming DCIS are more likely to progress to invasive cancers than are erbB-2-negatrvQ lesions, whereas erfoB-2-negative comedo DCIS are more likely to progress than are erbB-2-positive comedo DCIS. Once again, this suggests complementation groups, a requirement for coexpression of particular combinations of genotypic and phenotypic characteristics in order for cancer to develop and progress. {pagebreak}
p53 Several studies using antibodies to detect p53 protein indicate that p53 mutations are rare in benign lesions (Bartek et al., 1990; Heyderman and Dagg, 1991; Barbareschi et al., 1992; Eriksson et al., 1994; Stephenson et al., 1994; Umekita et al., 1994; Schmitt et al., 1995; Younes et al., 1995; Chitemerere et al., 1996; Siziopikou et al., 1996).
The total incidence of staining in these combined studies was 47/646 for benign lesions but most studies included fibroadenomas, which are frequently positive (Younes et al., 1995), as well as hyperplasias. In studies of hyperplastic lesions, only two of 80 specimens (2.5%) of PDWA and one of 108 atypical hyperplastic lesions were positive (Heyderman and Dagg, 1991; Umekita et al., 1994; Schmitt et al., 1995; Siziopikou et al., 1996).
DCIS is more frequently positive, with a total of 58 of 300 lesions staining for p53 (Bartek et al., 1990; Eriksson etal., 1994; Umekita etal., 1994; Leal etal., 1995; Schmitt etal., 1995; Chitemerere et al., 1996; Albonico et al., 1996; Siziopikou et al., 1996), and the proportion of invasive cancer-positive for p53 is higher yet; a total of 180 of 734 in total from a number of studies (Bartek et al., 1990; Heyderman and Dagg, 1991; Eriksson et al., 1994; Seth et al., 1994; Stephenson et al, 1994; Umekita et al., 1994; Younes et al., 1995; Nakopoulou et al., 1996). Seth et al. (1994) revealed that benign lesions, previously removed from two patients with p53-positive invasive cancers, were negative for p53.
The fact that CIS and carcinoma are similar inp53 expression but that hyperplastic lesions are rarely positive suggest ihaipSS mutation, like erbB-2, is not an early event in breast disease.
myc
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C-myc is amplified in about 20% of breast cancers (Garcia et al., 1989; Berns et al., 1992). Interestingly, only 1% of cases are positive for both erbB-2 and c-myc (Garcia et al., 1989; Berns et al., 1992), again indicating at least two distict molecular pathways to cancer. Although erbB-2 amplification is a useful prognostic factor for ER-negative cases, c-myc amplification is a useful prognostic factor for ER+ cases (Berns et al., 1992). Unlike erbB-2, c-myc amplification occurs early in proliferative breast disease (Agnantisetal., 1992;Escotetal., 1993;Hehiretal., 1993; Pechoux et al., 1994; Brem et al., 1977).
Myc expression is induced by estrogen and appears to be hyper-responsive in atypical hyperplasia in that expression is very high during the follicular phase, but not the luteal phase, of the menstrual cycle in atypical hyperplasia relative to other benign lesions (Escot et al., 1993). This study also found that myc expression was significantly higher in benign lesions of patients with a first-degree family history of breast cancer.
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C-myc amplification alters the reponse of breast epithelial cells to growth factors. EGF and FGF, which are normally mitogenic, transform cells that overexpress c-myc (reviewed in Dickson et al., 1992). Overexpression of c-myc in benign breast lesions may identify a high-risk subset as suggested by a finding of Hehir and colleagues: 62% of benign lesions from patients subsequently developing breast cancer were c-myc-positive, compared to 13% from patients who remained cancer-free. (1993).
Cyclin D1/PRAD1 Cyclin D1/PRAD1 is a cell cycle regulator necessary for Gl progression. The protein is overexpressed in one-third to one-half of invasive breast cancers as detected by immunohistochemistry (Bartkova et al., 1994, 1995; Zhang et al., 1994; Mcintosh et al., 1995; Zukerberg et al., 1995). Overexpression appears to first occur at DCIS (Bartkova et al., 1995; Weinstat-Saslow et al., 1995) and, in 37 cases of mixed DCIS and invasive carcinoma, was concordant in both invasive and noninvasive components (Bartkova et al., 1995). Elevated levels of PRADl mRNA were detected by in situ hybridization in proliferative disease, but PDWA and atypical hyperplasia were similar (18% in both; Weinstat-Saslow et al., 1995). The latter study revealed elevated PRADl mRNA in 76% of noncomedo DCIS, 87% of comedo DCIS, and 83% of invasive cancer. Thus, overexpression of PRADl, like p53 and erbB2, is associated with rapid progression to the DCIS stage. {pagebreak}
Ras Ras genes, Ha-ras, N-ras, and Ki-ras, encode for 21-kDa proteins important in signal transduction. Following binding of growth factors to cell surface receptor tyrosine kinases, p21 is transiently activated by phosphorylation and activates downstream serine/threonine kinases such as mitogen-activated protein (MAP) kinases and Raf-1, which in turn translocate to the nucleus where nuclear transcription factors such as Fos and Jun are phosphorylated/regulated. Activating mutations of ms result in a p21 protein that remains phosphorylated, maintaining active signal transduction pathways , in the absence of external stimuli.
Ras mutations are common in human cancer, occurring in approximately 30% of all cancers combined. However, mutated ras is much more prevalent in some types than in others. Whereas 90% of pancreatic cancers have a mutated ras gene (Almoguera et al., 1988), fewer than 5% of breast cancers do so (Kraus et al., 1984; Kozma etal., 1987;Rochlitzetal., 1989;Prosperietal., 1990; Clark and Der, 1995). Nevertheless, ras may be very important in breast cancer. The p21 ras protein is frequently overexpressed in breast cancer (Horan Hand et al., 1984; DeBortoli et al., 1985) and overexpression is significantly correlated with poor clinical prognosis (Clair etal., 1987; QuerzoU etal., 1988; Dati etal., 1991; Bland etal., 1995).
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Over-expression of p21 ras protein occurs early in the development of breast disease (Ohuchi et al., 1986; Spandidos et al., 1987; Agnantis et al., 1992; Going et al., 1992; Pechoux et al., 1994). Normal breast epitheUum (Spandidos et al., 1987) and lactating breast epithelium (Thor et al., 1986) do not express sufficient p21 ras to be identified, and only 1% of cells in fibrocystic disease without hyperplasia stain positive for ras (Ohuchi et al., 1986). Cystic disease associated with apocrine metaplasia is more often positive (Agnantis et al., 1992). As the stage of proliferative disease advances, the proportion of cells positive for ras increases from 18% for PDWA to 34% for atypical hyperplasia, 54% for CIS, and 62% for invasive carcinoma (Ohuchi et al., 1986).
Differences in the Ohuchi study were statistically significant at each sequential stage: fibrocystic disease versus PDWA, P<0.01; PDWA versus atypical hyperplasia, P<0.05; and atypical hyperplasia versus carcinoma (Pooled invasive and CIS), P<0.01; there was no difference in ras expression between CIS and invasive carcinoma. A more recent study confirmed the stepwise increase in ras expression based both on numbers of positive cells and intensity of staining (Going et al., 1992). As in the earlier study, significant overexpression of ras was detected in PDWA.
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Since numerous studies implicate ras function in PBD and breast cancer, it is curious that mutated ras is so infrequent. Perhaps breast is very susceptible to even minor disruptions in the ras pathway that could result from a number of genetic events, whereas pancreatic cells, for example, are made malignant only by full ras activation. If we assume that the rate of mutation of ras in breast cells is the same as in pancreatic cells, the number of breast cancers with mutated ras should be similar to the number of pancreatic cancers with mutated ras, suggesting that the low percentage of mutant ras breast cancers reflects the greater number of alternative complementation groups that can lead to this disease.
In the United States, the annual incidence of pancreatic cancers in white women is 7.5 per 100,000 compared to 113 breast cancers per 100,000 women (age adjusted) (Devesa et al., 1995). Thus, the incidence of mutant ras in breast cancer (5.65 cases per 100,000, assuming 5% have mutant ras) is similar to the incidence of mutant ras in pancreatic cancers (6.75 cases per 100,000, assuming 90% have mutant ras). Furthermore, mutations in a number of the components of the ras signal transduction pathway, including upstream receptor tyrosine kinases (eg., PDGFR, EGFR) and downstream serine/threonine kinases or transcription factors, are functionally equivalent to ras mutation (Clark and Der, 1995). Perhaps breast epithehum has a number of genes (e.g., receptor tyrosine kinases) active that pancreatic cells do not so that more genes are at risk in breast cancer cells which, if mutated, are surrogates for activated ras. {pagebreak}
BRCA1 BRCA1 mutations are present in approximately three-fourths of families with ovarian and breast cancer and in about half of families with only breast cancer. The molecule has a zinc-binding ring finger domain suggesting a function in regulation of transcription, but the protein has also been reported to be a secreted product that is able to inhibit tumor cell growth (Ezzell, 1996; Holt et al., 1996; Jensen, R.A. et al., 1996). Athough a single mutation has been found in 1% of the Ashkenase Jewish population, over 100 mutations have been identified, many of which occur in only one or two families (CoUins, 1996). Not all BRCAl mutations are equal.
Mutations in either the amino terminal or carboxy terminal conserved domains result in tumors with higher proliferation rates than mutations at other sites (Sobol et al., 1996). Furthermore, cancer grade segregates by family, some giving rise to more proliferative, aggressive invasive carcinoma than others (Eisinger et al., 1996).
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In a study of 202 cases from 36 BRCA1 breast cancer families, only four pure CIS lesions were found, two of which were sporadic cancers, that is, their hosts were not carriers of the mutant alleles (Sun et al., 1996). This finding suggests that, if present in BRCAl patients, DCIS is a very transient stage that rapidly progresses to invasive carcinoma.
BRCAl is seldom mutated in sporadic breast cancer (Xu and Solomon, 1996).
However, allelic imbalance at the BRCAl locus was seen in 74% of DCIS cases (Munn et al., 1996). Thus, the role of BRCAl in sporadic breast cancer is still undetermined.
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BRCA2 BRCA2 is a second hereditary breast cancer gene and is involved in site-specific breast cancer families. BRCA2 may account for most of the male breast cancer families but was reported to be mutated in only eight of 49 families with breast cancer only (Phelan et al., 1996). Like BRCAl, the role of BRCA2 in sporadic breast cancer is unclear. Although loss of heterozygosity at the BRCA2 locus is common in sporadic breast cancer, mutations in BRCA2 are rare (Lancaster et al., 1996; Miki et al., 1996).
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