The requirement of integrins for breast epithelial proliferation

Abstract Epithelial cells forming mammary gland ducts and alveoli require adhesion to the extracellular matrix for their function. Mammary epithelial cells need β 1-integrins for normal cell cycle regulation. However, the role of β 1-integrins in tumorigenesis has not been fully resolved. β 1-integrin is necessary for tumour formation in transgenic mice expressing the Polyomavirus Middle T antigen, but it is dispensable in those overexpressing ErbB2. This suggests that some oncogenes can manage without β 1-integrin to proliferate and form tumours, while others still require it. Here we have developed a model to test whether expression of an oncogene can surpass the need for β 1-integrin to drive proliferation. We co-expressed the ErbB2 or Akt oncogenes with shRNA to target β 1-integrin in mammary epithelial cells, and found that they show a differential dependence on β 1-integrin for cell division. Moreover, we identified a key proliferative role of the Rac1-Pak axis downstream of β 1-integrin signalling. Our data suggest that, in mammary epithelial cells, oncogenes with the ability to signal to Pak surpass the requirement of integrins for malignant transformation. This highlights the importance of using the correct combination therapy for breast cancer, depending on the oncogenes expressed in the tumour.