Hormone therapy and the breast - aspects on proliferation, apoptosis and mammographic density

Sammanfattning: Breast cancer is the major malignancy among women in the western world. The breast is clearly a target organ for sex steroid hormones and hormonal treatments have been associated with an increased risk of breast cancer. Still, basic knowledge as to how sex steroids influence the normal breast is remarkably poor. The balance between proliferation and apoptosis is important for breast cell homeostasis. Mammographic breast density has been identified as a strong and independent risk factor. The aims of this work were to compare the effects of different hormonal treatments on breast cell proliferation, and mammographic density in postmenopausal women and to explore possible associations with hormonal and constitutional factors. Further, to investigate apoptotic mechanisms in a primate model. The fine needle aspiration biopsy technique was found to be a useful tool to evaluate the proliferative response to hormonal treatment in the normal breasts of postmenopausal women. During continuous combined estrogen/progestogen therapy there was on average a 3-4 fold increase in proliferation as expressed by the percentage of MIB-1 positive cells. There was also a significant increase in mammographic density and a positive correlation between proliferation and density. Two progestogens with different characteristics (norethisterone and dienogest) had quite the same impact on the breast when given in continuous combination with estrogen. Tibolone, a compound with estrogenic, progestogenic and androgenic properties had less impact on breast cell proliferation than conventional hormone therapy. Alternative regimens had different effects on p53 expression and apoptotic activity in the monkey breast. A combination of increased proliferation and decreased apoptosis could be one mechanism to explain the excess risk of breast cancer during estrogen/progestogen treatment. Certain constitutional and hormonal factors were found to be predictive of breast reactivity and older women with a low body mass index responded stronger to treatment. Estrogen levels had a positive and androgens a negative association to density and proliferation. From a clinical perspective, increased breast cell proliferation and mammographic density should be regarded as unwanted and potentially hazardous side-effects during hormonal treatment. Efforts should be made to identify those women with an adverse response to treatment as well as therapeutic principles with the least possible influence on the breast.