SummaryLow-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.

It is well accepted that cancer arises in a multistep fashion in which exposure to environmental carcinogens is a major etiological factor. The aim of this work was to establish an experimental breast cancer model in order to understand the mechanism of neoplastic transformation induced by high LET radiation in the presence of 17beta-estradiol (E). Immortalized human breast cells (MCF-10F) were exposed to low doses of high LET alpha particles (150 keV/microm) and subsequently cultured in the presence or absence of E for periods of up to 10 months post-irradiation. MCF-10F cells irradiated with either a single 60 cGy dose or 60/60 cGy doses of alpha particles showed gradual phenotypic changes including altered morphology, increase in cell proliferation relative to the control, anchorage-independent growth and invasive capability before becoming tumorigenic in nude mice. In alpha particle-irradiated cells and in those cells subsequently cultured in the presence of E, increased BRCA1, BRCA2 and RAD51 expression were detected by immunofluorescence staining and quantified by confocal microscopy. These studies showed that high LET radiation such as that emitted by radon progeny, in the presence of estrogen, induced a cascade of events indicative of cell transformation and tumorigenicity in human breast epithelial cells.

Breast cancer is one of the leading causes of mortality among women worldwide due to aggressive behavior, early metastasis, resistance to existing chemotherapeutic agent and high mortality rate. Doxorubicin (Dox) is a powerful antitumoral drug. It is one of the most active agents for treatment of breast cancer. The aim of the present study was to evaluate the influence of Dox in apoptosis and oxidative stress in the breast cancer cell lines MCF-10F, MCF-7 and MDA-MB-231. These studies showed that Dox decreased anti-apoptotic Bcl-2 protein expression and affected oxidative stress by increasing hydrogen peroxide production and simultaneously decreasing NF-κB gene and protein expression in MCF-7, a tumorigenic triple-positive cell line. Results also indicated that Dox induced apoptosis by upregulating Bax, caspase-8 and caspase-3 and downregulation of Bcl-2 protein expression. On the contrary, ROS damage decreased by increasing SOD2 gene and protein expression and hydrogen peroxide production with parallel NF-κB protein expression decrease in MDA-MB-231, a tumorigenic triple-negative breast cancer cell line. It can be concluded that Dox activated apoptosis by inducing proteolytic processing of Bcl-2 family, caspases and simultaneously decreased oxidative stress by influencing ROS damage in MCF-7 and MDA-MB-231 cell lines.

The present study was carried out to determine whether human breast epithelial cells (HBEC) are transformed by chemicals that have been proven to be carcinogenic in other model systems. A spontaneously immortalized human breast epithelial cell line, MCF-10F, was treated with dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (B[a]P), N-methyl-N-nitrosoguanidine (MNNG) or N-methyl-N-nitrosourea (NMU) for 24 h. MCF-7 and T24 malignant cell lines were used as positive controls. All the carcinogens induced alterations in both cell morphology and pattern of growth, increased growth rate and anchorage-independent growth in agar-methocel, which became evident by the 8th to 10th passages post-treatment, at approximately 157 days in culture. Colonies formed in agar-methocel were isolated and expanded. The following clones were successfully grown: D1, D2 and D3, from DMBA, M4 from MNNG, and BP1, BP2, BP5, BP6, BP7, and BP10 from B[a]P treated cells. From clones BP1 and BP2, selected cell populations were isolated and the derived cell lines or clones were named BP1-E and BP2-B respectively; the D3-1 cell line was derived from clone D3. BP1 and BP1-E clones showed increased anchorage-independent growth, chemotaxis and invasiveness. Clone D3-1 showed increased chemotactic and invasive capabilities, but to a lesser degree than BP1-E. The tumorigenic potential of the cells was tested by inoculation into SCID mice. MCF-7, T24 and BP1-E cells formed tumors in 100% of the SCID mice at 28, 10 and 101 days of inoculation respectively. None of the other clones formed tumors. It was concluded that both polycyclic hydrocarbons and aromatic amines induced in the immortal cells MCF-10F changes indicative of neoplastic transformation. Our data show that the phenotypes associated with neoplastic transformation appear in a progressive fashion, and that the emergence of clones is associated with the expression of higher proliferative rate, anchorage independence, chemotactic and chemoinvasive abilities and, in certain cases, tumorigenicity.