Breast Cancer, inflammation and proliferation

Breast cancer is the most frequent malignant tumor of women in Europe and the United States. Standard treatment modalities have improved the overall outlook and quality of life for women with breast cancer; however, the fact that 40% still die of this illness highlights the need for new therapeutic approaches and identification of new therapeutic targets. While genetic and epigenetic changes in genes that regulate mammary epithelial cell proliferation, survival, polarity and/or differentiation are probable 'initiators' of breast carcinogenesis, several lines of evidence indicate that stromal cell responses in premalignant mammary tissue may 'promote' progression to cancer and/or the metastatic capability of malignant mammary epithelial cells.

As early as 1863, Virchow first postulated that cancer originates at sites of chronic inflammation, in part based on his hypothesis that some classes of irritants causing inflammation also enhance cell proliferation. Historically, leukocytes found in and around developing tumors were thought to represent an attempt by the host to eradicate transformed neoplastic cells. Certain leukocytes, such as cytotoxic T lymphocytes (CTLs) and NK cells, undeniably play a vital function in constraining tumor development, and as such it has been postulated that many more neoplasms arise than those that eventually develop to fully malignant disease. Epidemiologic data support this contention, as evidenced by the increased incidence of viral-associated cancers, including human papillomavirus-related cervical and squamous carcinoma, herpesvirus-8-associated Kaposi's sarcoma and Epstein-Barr virus-related non-Hodgkin's lymphoma in immunocompromised individuals. Similar to viral-associated cancers, there are data revealing an increased incidence of carcinogen-associated cancers in immune-compromised populations, including melanoma and lung adenocarcinoma. Where carcinogen exposure and pathogen exposure are not thought to be etiologic factors, however, immune-compromised women exhibit reduced relative risk for common epithelial cancers, including breast adenocarcinoma. Together, these epidemiological studies indicate that the overall risk for, and development of, (breast) cancer may, in part, be regulated by the immune status of the individual.

Histochemical detection of T lymphocytes in archival human carcinoma tissues has revealed that they also are commonly associated with developing carcinomas; however, the prognostic significance of T-cell infiltrations during breast carcinogenesis is subject to great debate. While B cells appear to represent the predominant lymphocyte during early breast cancer progression, infiltrating T lymphocytes (both CD4⁺ and CD8⁺) are more extensive in higher grade DCIS and invasive carcinomas.

The extent of T-cell infiltration into invasive breast carcinomas has been reported to range from 1% to 45% of the total cellular mass. In rapidly proliferating tumors, the presence of T lymphocytes (by histopathological determination) at tumor sites is a good prognostic indicator when compared with nonimmunogenic tumors, and correlates with auxillary lymph node negativity, a smaller tumor diameter, a lower histological grade and recurrence-free survival – therefore supporting an overall role for T cells in immune surveillance. The exact composition of T lymphocyte infiltration varies greatly, however, and may profoundly affect disease progression and overall patient survival.

While natural killer cells and CD8+ cytotoxic T cells surrounding DCIS and malignant breast cancer express the Fas ligand (FasL), breast cancer cells express at the same time the corresponding receptor Fas (CD95). Despite the presence of these two critical components for the initiation of the extrinsic death pathway breast cancer cells do not enter the apoptotic pathway. This fascinating observation initiated our detailed study on the extrinsic pathway in breast cancer cells:

Activation of caspases, aspartyl-specific cysteine proteases, is the hallmark for the execution of apoptosis. The molecular mechanisms regulating the autocatalytic activation of the initiator caspase-8, which is synthesized as inactive zymogen, are not well understood. Here, we demonstrate that capase-8 is a substrate of Cdk1/cyclin B1, which periodically phosphorylates caspase-8 during the cell cycle. Applying an RNAi approach targeting cyclin B1 or treating cells with the Cdk1-specifc inhibitor R0–3306, we show that Fas-mediated induction of apoptosis is greatly increased. Replacing endogenous caspase-8 by a mutant mimicking the phosphorylation protected cells against Fas-induced apoptosis, which correlates to a reduced generation of the p11 subunit suggesting that a phosphorylation event, which is located close to the cleavage site used for p11 liberation, inhibits the processing of caspase-8. In human breast cancer caspase-8 was also found to be phosphorylated proposing a new mechanism by which Cdk1/cyclin B1 activity regulates the threshold for activation of the extrinsic death pathway and suppresses apoptosis during mitosis in breast cancer.