Tumour markers in breast carcinoma correlate with grade rather than with invasiveness.

Department of Surgery, University Hospital Uppsala, S-751 85 Uppsala, Sweden.
British Journal of Cancer (Impact Factor: 4.82). 10/2001; 85(6):869-74. DOI: 10.1054/bjoc.2001.1995
Source: PubMed

ABSTRACT Ductal breast carcinoma in situ (DCIS) is regarded as a precursor to invasive breast cancer. The progression from in situ to invasive cancer is however little understood. We compared some tumour markers in invasive and in situ breast carcinomas trying to find steps in this progression. We designed a semi-experimental setting and compared histopathological grading and tumour marker expression in pure DCIS (n = 194), small invasive lesions (n = 127) and lesions with both an invasive and in situ component (n = 305). Grading was done according to the Elston-Ellis and EORTC classification systems, respectively. Immunohistochemical staining was conducted for p53, c-erbB-2, Ki-67, ER, PR, bcl-2 and angiogenesis. All markers correlated with grade rather than with invasiveness. No marker was clearly associated with the progression from in situ to invasiveness. The expression of tumour markers was almost identical in the 2 components of mixed lesions. DCIS as a group showed a more 'malignant picture' than invasive cancer according to the markers, probably, due to a higher proportion of poorly differentiated lesions. The step between in situ and invasive cancer seems to occur independently of tumour grade. The results suggest that well-differentiated DCIS progress to well-differentiated invasive cancer and poorly differentiated DCIS progress to poorly differentiated invasive cancer.

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    ABSTRACT: Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16(INK4); replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional "passenger" errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se; bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of "passenger" genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.
    Cell cycle (Georgetown, Tex.) 11/2014; 13(21):3423-3435. · 5.24 Impact Factor
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    ABSTRACT: Experimental examination of the agents and processes that may propel or prevent human breast carcinogenesis can be facilitated by in vitro model systems of transformation, starting with normal cells, that accurately reflect the in vivo biology. Model systems that can replicate the types of alterations seen during in vivo progression offer the potential to understand the mechanisms underlying progression and to examine possible means of individualized prevention and treatment. To this end, we have developed an experimentally tractable human mammary epithelial cell (HMEC) culture system that has been used to examine the normal processes governing HMEC growth, differentiation, aging, and senescence, and how these normal processes are altered during immortal and malignant transformation. Isogenic cells at different stages of multistep carcinogenesis were generated by exposing normal finite lifespan HMEC to a variety of oncogenic agents that may play an etiologic role in breast cancer. Examination of the molecular alterations present at each stage has indicated that this model is consistent with observed multistep carcinogenesis in vivo. We have seen that varying target cell type, and oncogenic agents used, can lead to multiple distinct molecular pathways of transformation, although the full diversity of human breast cancer cell types has not yet been generated in culture models. Using this integrated system, we have formulated a comprehensive model of the proliferative barriers normal HMEC must overcome to gain immortality and malignancy. Our data provide insights on acquisition of cancer-associated properties and suggest that the most crucial step in breast cancer progression involves the transition from a finite to indefinite lifespan. For example, we see that genomic instability originates in finite lifespan HMEC when telomeres become critically short and engage in telomeric associations, and is then maintained in resultant immortalized and malignant lines. Direct genomic targeting of the tumor suppressive senescence barriers can produce lines lacking gross genomic errors, supporting the hypothesis that genomic instability is a mechanism to generate cancer-causing errors, but is not necessary per se. Immortalization through telomerase reactivation was also associated with acquisition of resistance to TGFβ growth inhibition and to oncogene-induced senescence (OIS), and with large-scale changes in gene expression and epigenetic markers. Being able to examine the progressive changes that fuel malignancy, starting with normal cells, provides an integrated perspective that can reveal novel information on the origins and consequences of individual cancer-associated aberrations.
    Cell and Molecular Biology of Breast Cancer,, Edited by H. Schatten, 10/2013: chapter An Integrated Human Mammary Epithelial Cell Culture System for Studying Carcinogenesis and Aging: pages 323-361; Springer.
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    ABSTRACT: Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers. Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied. Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers). Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.
    International journal of breast cancer. 01/2014; 2014:581706.


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