MYC gene amplification is often acquired in lethal distant breast cancer metastases of unamplified primary tumors

Abstract

In breast cancer, amplification of MYC is consistently observed in aggressive forms of disease and correlates with poor prognosis and distant metastases. However, to date, a systematic analysis of MYC amplification in metastatic breast cancers has not been reported. Specifically, whether the MYC amplification status may change in metastases in comparison to the corresponding primary breast tumor, and potential variability among different metastases within the same patient have also not been assessed. We generated single patient tissue microarrays consisting of both primary breast carcinomas and multiple matched systemic metastases from 15 patients through our previously described rapid autopsy program. In total, the 15 tissue microarrays contained 145 primary tumor spots and 778 spots derived from 180 different metastases. In addition, 2 separate tissue microarrays were constructed composed of 10 matched primary breast cancers and corresponding solitary metastases sampled not at autopsy but rather in routine surgical resections. These 2 tissue microarrays totaled 50 primary tumor spots and 86 metastatic tumor spots. For each case, hormone receptor status, HER2/neu, EGFR and CK5/6 expression were assessed, and the cases were characterized as luminal, basal-like or HER2 based on published criteria. Both fluorescence in situ hybridization and immunohistochemistry for MYC was performed on all cases. Of the 25 cases, 24 were evaluable. While 4 of 24 primary tumors (16%) demonstrated MYC amplification, an additional 6 (25% of total evaluable cases) acquired MYC amplification in their systemic metastases. Of note, there was remarkably little heterogeneity in MYC copy number among different metastases from the same patient. MYC immunoreactivity was increased in metastases relative to matched primaries in the surgical cohort, though there was not a perfect correlation with MYC amplification. In conclusion, amplification of MYC is a frequent event in breast cancer, but occurs more frequently as a diffuse, acquired event in metastatic disease than in the corresponding primary. These observations underscore the importance of MYC in breast cancer progression/metastasis, as well as its relevance as a potential therapeutic target in otherwise incurable metastatic disease.

MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

“…However, our study demonstrated that, despite MYC expression spanning accross all the intrinsic subtypes of breast cancer determined in our primary and metastatic samples, there was a tendency toward a higher MYC positivity rate in the luminal subtype, as compared to the other subtypes, although this tendency was not statistically significant (P=0.13). This result contradicts those of other studies demonstrating a clear association between MYC amplification and ER-negative or basal breast cancers (9,(29)(30)(31). It is possible that, in luminal A tumors displaying low Ki67 scores, MYC expression reflects biological characteristics of the tumor cell population other than its proliferative state.…”

“…protein overexpression in the epithelial component of breast cancer (6)(7)(8)(9)(22)(23)(24). However, we were unable to identify any correlation between MYC expression and axillary lymph node positivity in our series, confirming the results of previous studies (5,6,25).…”

“…Although detailed biomarker profiles of the metastatic lesions of breast carcinomas are scarce in the literature, certain studies report a high incidence of MYC overexpression/amplification in the distant metastases of invasive ductal carcinoma (6,8,9). However, whether the MYC status may change in lymph node metastases compared to that in the corresponding primary breast tumor has not been clearly determined.…”

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…[44][45][46][47][48][49][50][51][52][53][54][55] Both OSM/STAT3-and TGFb-induced senescence require the repression of MYC. 40,[56][57][58][59] Our lab has previously demonstrated that the expression of MYC from a constitutive promoter prevents OSM-or RAS-induced senescence and alters the response of HMEC to persistent oncogenic stimuli, from growth suppressive to growth promoting.…”

Mammalian MYC Proteins and Cancer

“…This manner of MYC induction is fairly common in cancer, affects all MYC family members, and can take the form of small focal amplifications [126,127], large amplifications [128], and doubleminute chromosomes [129]. Although increasing the number of copies of MYC does not always correlate with MYC overexpression [130,131], the frequency with which MYC gene amplification occurs and the correlation of this event with metastatic disease and poor prognosis [132] strongly indicate a direct role for MYC gene amplification in many human malignancies.…”