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The Src family kinases (SFKs) are believed to play critical roles in malignant transformation, as well as in growth, invasion and dissemination of neoplastic tissue. Inhibition of SFK-mediated signal transduction and activation of downstream targets inhibits tumor progression. To determine whether constitutive activity of SFK per se is sufficient to induce tumorigenesis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of the SFK-negative regulator csk (Csk-K5 mice). Even though expression levels of SFKs were lower in C-terminal Src kinase (Csk)-null keratinocytes, activity levels were higher than in control keratinocytes. At the age of 3 months, all Csk-K5 mice displayed signs of chronic inflammation in dermis and epidermal hyperplasia. About 19% of Csk-K5 mice (7 out of 36) developed papillomatous lesions. However, these lesions did not show any signs of neoplastic transformation over the next 8 months. Epidermal hyperplasia and hyperkeratosis in Csk-K5 mice were associated with an increased number of stem cells in the interfollicular epidermis, an increased proliferation of basal keratinocytes and a delayed terminal differentiation of the suprabasal keratinocytes. Our results clearly demonstrate that even though SFK-mediated signaling promotes tumor progression, elevated activity of SFKs in vivo alone is not sufficient to induce neoplastic transformation.

The phospholipid (PL) content was 4-fold higher while the triacylglycerol (TG) content tended to be 65% lower in human breast cancer tissues as compared with non-cancerous reference parts from excised breast tissues. The variation in TG content among breast tissues was very large while that of PL was relatively small. The fatty acid compositions of PL were significantly different between the cancer and reference tissues; the proportions of octadecenoate (18:1), docosahexaenoate (22:6n-3), the total n-3 fatty acids and the n-3/n-6 ratio, but not the proportion of arachidonate (20:4n-6), were significantly higher in the major PL of cancer tissues as compared with those of the reference tissues. No significant differences were observed in the proportion of the major fatty acids of TG in these tissues. The turnover of lipids was faster in the cancer tissues than in the reference tissues. The turnover of TG was faster than that of PL in the cancer tissues, whereas the opposite was true in the reference tissues, indicating significant differences in lipid metabolism between these tissues. A striking difference in the n-3 and n-6 fatty acids of the reference tissues noted for Japanese and Finnish women is discussed in relation to the roles of eicosanoids and eicosanoid precursors in mammary carcinogenesis.